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1
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Aljuhani A, Alsehli M, Seleem MA, Alraqa SY, Ahmed HEA, Rezki N, Aouad MR. Exploring of N-phthalimide-linked 1,2,3-triazole analogues with promising -anti-SARS-CoV-2 activity: synthesis, biological screening, and molecular modelling studies. J Enzyme Inhib Med Chem 2024; 39:2351861. [PMID: 38847308 PMCID: PMC11164105 DOI: 10.1080/14756366.2024.2351861] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2023] [Accepted: 04/29/2024] [Indexed: 06/12/2024] Open
Abstract
In this study, a library of phthalimide Schiff base linked to 1,4-disubstituted-1,2,3-triazoles was designed, synthesised, and characterised by different spectral analyses. All analogues have been introduced for in vitro assay of their antiviral activity against COVID-19 virus using Vero cell as incubator with different concentrations. The data revealed most of these derivatives showed potent cellular anti-COVID-19 activity and prevent viral growth by more than 90% at two different concentrations with no or weak cytotoxic effect on Vero cells. Furthermore, in vitro assay was done against this enzyme for all analogues and the results showed two of them have IC50 data by 90 µM inhibitory activity. An extensive molecular docking simulation was run to analyse their antiviral mechanism that found the proper non-covalent interaction within the Mpro protease enzyme. Finally, we profiled two reversible inhibitors, COOH and F substituted analogues that might be promising drug candidates for further development have been discovered.
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Affiliation(s)
| | - Mosa Alsehli
- Chemistry Department, College of Sciences, Taibah University, Saudi Arabia
| | - Mohamed A. Seleem
- Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Al-Azhar University, Nasr, City, Cairo, Egypt
| | - Shaya Y. Alraqa
- Chemistry Department, College of Sciences, Taibah University, Saudi Arabia
| | - Hany E. A. Ahmed
- Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Al-Azhar University, Nasr, City, Cairo, Egypt
| | - Nadjet Rezki
- Chemistry Department, College of Sciences, Taibah University, Saudi Arabia
| | - Mohamed R. Aouad
- Chemistry Department, College of Sciences, Taibah University, Saudi Arabia
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2
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Jagtap P, Meena VK, Sambhare S, Basu A, Abraham P, Cherian S. Exploring Niclosamide as a Multi-target Drug Against SARS-CoV-2: Molecular Dynamics Simulation Studies on Host and Viral Proteins. Mol Biotechnol 2024:10.1007/s12033-024-01296-2. [PMID: 39373955 DOI: 10.1007/s12033-024-01296-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2024] [Accepted: 09/23/2024] [Indexed: 10/08/2024]
Abstract
Niclosamide has emerged as a promising repurposed drug against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). In vitro studies suggested that niclosamide inhibits the host transmembrane protein 16F (hTMEM16F), crucial for lipid scramblase activity, which consequently reduces syncytia formation that aids viral spread. Based on other in vitro reports, niclosamide may also target viral proteases such as papain-like protease (PLpro) and main protease (Mpro), essential for viral replication and maturation. However, the precise interactions by which niclosamide interacts with these multiple targets remain largely unclear. Docking and molecular dynamics (MD) simulation studies were undertaken based on a homology model of the hTMEM16F and available crystal structures of SARS-CoV-2 PLpro and Mpro. Niclosamide was observed to bind stably throughout a 400 ns MD simulation at the extracellular exit gate of the hTMEM16F tunnel, forming crucial interactions with residues spanning the TM1-TM2 loop (Gln350), TM3 (Phe481), and TM5-TM6 loop (Lys573, Glu594, and Asp596). Among the SARS-CoV-2 proteases, niclosamide was found to interact effectively with conserved active site residues of PLpro (Tyr268), exhibiting better stability in comparison to the control inhibitor, GRL0617. In conclusion, our in silico analyses support niclosamide as a multi-targeted drug inhibiting viral and host proteins involved in SARS-CoV-2 infections.
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Affiliation(s)
- Prachi Jagtap
- Bioinformatics & Data Management Group, ICMR National Institute of Virology, 20A Dr. Ambedkar Road, Pune, Maharashtra, 411 001, India
| | - Virendra Kumar Meena
- ICMR National Institute of Virology, 20A Dr. Ambedkar Road, Pune, Maharashtra, 411 001, India
| | - Susmit Sambhare
- ICMR National Institute of Virology, 20A Dr. Ambedkar Road, Pune, Maharashtra, 411 001, India
| | - Atanu Basu
- ICMR National Institute of Virology, 20A Dr. Ambedkar Road, Pune, Maharashtra, 411 001, India
| | - Priya Abraham
- Christian Medical College, Vellore, Tamil Nadu, India
| | - Sarah Cherian
- Bioinformatics & Data Management Group, ICMR National Institute of Virology, 20A Dr. Ambedkar Road, Pune, Maharashtra, 411 001, India.
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3
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Sales AH, Fu I, Durandin A, Ciervo S, Lupoli TJ, Shafirovich V, Broyde S, Geacintov NE. Variable Inhibition of DNA Unwinding Rates Catalyzed by the SARS-CoV-2 Helicase Nsp13 by Structurally Distinct Single DNA Lesions. Int J Mol Sci 2024; 25:7930. [PMID: 39063172 PMCID: PMC11276626 DOI: 10.3390/ijms25147930] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2024] [Revised: 07/09/2024] [Accepted: 07/16/2024] [Indexed: 07/28/2024] Open
Abstract
The SARS-CoV-2 helicase, non-structural protein 13 (Nsp13), plays an essential role in viral replication, translocating in the 5' → 3' direction as it unwinds double-stranded RNA/DNA. We investigated the impact of structurally distinct DNA lesions on DNA unwinding catalyzed by Nsp13. The selected lesions include two benzo[a]pyrene (B[a]P)-derived dG adducts, the UV-induced cyclobutane pyrimidine dimer (CPD), and the pyrimidine (6-4) pyrimidone (6-4PP) photolesion. The experimentally observed unwinding rate constants (kobs) and processivities (P) were examined. Relative to undamaged DNA, the kobs values were diminished by factors of up to ~15 for B[a]P adducts but only by factors of ~2-5 for photolesions. A minor-groove-oriented B[a]P adduct showed the smallest impact on P, which decreased by ~11% compared to unmodified DNA, while an intercalated one reduced P by ~67%. However, the photolesions showed a greater impact on the processivities; notably, the CPD, with the highest kobs value, exhibited the lowest P, which was reduced by ~90%. Our findings thus show that DNA unwinding efficiencies are lesion-dependent and most strongly inhibited by the CPD, leading to the conclusion that processivity is a better measure of DNA lesions' inhibitory effects than unwinding rate constants.
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Affiliation(s)
- Ana H. Sales
- Chemistry Department, New York University, 31 Washington Place, New York, NY 10003, USA; (A.H.S.); (A.D.); (S.C.); (T.J.L.); (V.S.)
| | - Iwen Fu
- Biology Department, New York University, 24 Waverly Place, New York, NY 10003, USA; (I.F.); (S.B.)
| | - Alexander Durandin
- Chemistry Department, New York University, 31 Washington Place, New York, NY 10003, USA; (A.H.S.); (A.D.); (S.C.); (T.J.L.); (V.S.)
| | - Sam Ciervo
- Chemistry Department, New York University, 31 Washington Place, New York, NY 10003, USA; (A.H.S.); (A.D.); (S.C.); (T.J.L.); (V.S.)
| | - Tania J. Lupoli
- Chemistry Department, New York University, 31 Washington Place, New York, NY 10003, USA; (A.H.S.); (A.D.); (S.C.); (T.J.L.); (V.S.)
| | - Vladimir Shafirovich
- Chemistry Department, New York University, 31 Washington Place, New York, NY 10003, USA; (A.H.S.); (A.D.); (S.C.); (T.J.L.); (V.S.)
| | - Suse Broyde
- Biology Department, New York University, 24 Waverly Place, New York, NY 10003, USA; (I.F.); (S.B.)
| | - Nicholas E. Geacintov
- Chemistry Department, New York University, 31 Washington Place, New York, NY 10003, USA; (A.H.S.); (A.D.); (S.C.); (T.J.L.); (V.S.)
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Mao ND, Xu Y, Che H, Yao X, Gao Y, Wang C, Deng H, Hui Z, Zhang H, Ye XY. Design, synthesis and biological evaluation of novel 1,2,4a,5-tetrahydro-4H-benzo[b][1,4]oxazino[4,3-d][1,4]oxazine-based AAK1 inhibitors with anti-viral property against SARS-CoV-2. Eur J Med Chem 2024; 268:116232. [PMID: 38377825 DOI: 10.1016/j.ejmech.2024.116232] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2023] [Revised: 02/09/2024] [Accepted: 02/10/2024] [Indexed: 02/22/2024]
Abstract
Coronavirus entry into host cells hinges on the interaction between the spike glycoprotein of the virus and the cell-surface receptor angiotensin-converting enzyme 2 (ACE2), initiating the subsequent clathrin-mediated endocytosis (CME) pathway. AP-2-associated protein kinase 1 (AAK1) holds a pivotal role in this pathway, regulating CME by modulating the phosphorylation of the μ subunit of adaptor protein 2 (AP2M1). Herein, we report a series of novel AAK1 inhibitors based on previously reported 1,2,4a,5-tetrahydro-4H-benzo[b] [1,4]oxazino[4,3-d] [1,4]oxazine scaffold. Among 23 synthesized compounds, compound 12e is the most potent one with an IC50 value of 9.38 ± 0.34 nM against AAK1. The in vitro antiviral activity of 12e against SARS-CoV-2 was evaluated using a model involving SARS-CoV-2 pseudovirus infecting hACE2-HEK293 host cells. The results revealed that 12e was superior in vitro antiviral activity against SARS-CoV-2 entry into host cells when compared to SGC-AAK1-1 and LX9211, and its activity was comparable to that of a related and reference compound 8. Mechanistically, all AAK1 inhibitors attenuated AAK1-induced phosphorylation of AP2M1 threonine 156 and disrupted the direct interaction between AP2M1 and ACE2, ultimately inhibiting SARS-CoV-2 infection. Notably, compounds 8 and 12e exhibited a more potent effect in suppressing the phosphorylation of AP2M1 T156 and the interaction between AP2M1 and ACE2. In conclusion, novel AAK1 inhibitor 12e demonstrates significant efficacy in suppressing SARS-CoV-2 infection, and holds promise as a potential candidate for developing novel antiviral drugs against SARS-CoV-2 and other coronavirus infections.
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Affiliation(s)
- Nian-Dong Mao
- School of Pharmacy, Hangzhou Normal University, Hangzhou, Zhejiang, 311121, China; Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines, Engineering Laboratory of Development and Application of Traditional Chinese Medicines, Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, Hangzhou Normal University, Hangzhou, Zhejiang, 311121, China; School of Life and Environmental Sciences, Hangzhou Normal University, Hangzhou, Zhejiang, 311121, China
| | - Yueying Xu
- School of Pharmacy, Hangzhou Normal University, Hangzhou, Zhejiang, 311121, China; Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines, Engineering Laboratory of Development and Application of Traditional Chinese Medicines, Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, Hangzhou Normal University, Hangzhou, Zhejiang, 311121, China
| | - Hao Che
- School of Pharmacy, Hangzhou Normal University, Hangzhou, Zhejiang, 311121, China; Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines, Engineering Laboratory of Development and Application of Traditional Chinese Medicines, Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, Hangzhou Normal University, Hangzhou, Zhejiang, 311121, China
| | - Xia Yao
- School of Pharmacy, Hangzhou Normal University, Hangzhou, Zhejiang, 311121, China; Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines, Engineering Laboratory of Development and Application of Traditional Chinese Medicines, Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, Hangzhou Normal University, Hangzhou, Zhejiang, 311121, China
| | - Yuan Gao
- Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Chenchen Wang
- School of Life and Environmental Sciences, Hangzhou Normal University, Hangzhou, Zhejiang, 311121, China
| | - Haowen Deng
- School of Pharmacy, Hangzhou Normal University, Hangzhou, Zhejiang, 311121, China; Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines, Engineering Laboratory of Development and Application of Traditional Chinese Medicines, Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, Hangzhou Normal University, Hangzhou, Zhejiang, 311121, China
| | - Zi Hui
- School of Pharmacy, Hangzhou Normal University, Hangzhou, Zhejiang, 311121, China; Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines, Engineering Laboratory of Development and Application of Traditional Chinese Medicines, Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, Hangzhou Normal University, Hangzhou, Zhejiang, 311121, China.
| | - Hang Zhang
- School of Basic Medical Science, Hangzhou Normal University, Hangzhou, Zhejiang, 311121, China.
| | - Xiang-Yang Ye
- School of Pharmacy, Hangzhou Normal University, Hangzhou, Zhejiang, 311121, China; Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines, Engineering Laboratory of Development and Application of Traditional Chinese Medicines, Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, Hangzhou Normal University, Hangzhou, Zhejiang, 311121, China; School of Life and Environmental Sciences, Hangzhou Normal University, Hangzhou, Zhejiang, 311121, China.
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5
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Hu C. Marine natural products and human immunity: novel biomedical resources for anti-infection of SARS-CoV-2 and related cardiovascular disease. NATURAL PRODUCTS AND BIOPROSPECTING 2024; 14:12. [PMID: 38282092 PMCID: PMC10822835 DOI: 10.1007/s13659-024-00432-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/12/2023] [Accepted: 01/17/2024] [Indexed: 01/30/2024]
Abstract
Marine natural products (MNPs) and marine organisms include sea urchin, sea squirts or ascidians, sea cucumbers, sea snake, sponge, soft coral, marine algae, and microalgae. As vital biomedical resources for the discovery of marine drugs, bioactive molecules, and agents, these MNPs have bioactive potentials of antioxidant, anti-infection, anti-inflammatory, anticoagulant, anti-diabetic effects, cancer treatment, and improvement of human immunity. This article reviews the role of MNPs on anti-infection of coronavirus, SARS-CoV-2 and its major variants (such as Delta and Omicron) as well as tuberculosis, H. Pylori, and HIV infection, and as promising biomedical resources for infection related cardiovascular disease (irCVD), diabetes, and cancer. The anti-inflammatory mechanisms of current MNPs against SARS-CoV-2 infection are also discussed. Since the use of other chemical agents for COVID-19 treatment are associated with some adverse effects in cardiovascular system, MNPs have more therapeutic advantages. Herein, it's time to protect this ecosystem for better sustainable development in the new era of ocean economy. As huge, novel and promising biomedical resources for anti-infection of SARS-CoV-2 and irCVD, the novel potential mechanisms of MNPs may be through multiple targets and pathways regulating human immunity and inhibiting inflammation. In conclusion, MNPs are worthy of translational research for further clinical application.
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Affiliation(s)
- Chunsong Hu
- Department of Cardiovascular Medicine, Jiangxi Academy of Medical Science, Nanchang University, Hospital of Nanchang University, No. 461 Bayi Ave, Nanchang, 330006, Jiangxi, China.
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6
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Farrag M, Dwivedi R, Sharma P, Kumar D, Tandon R, Pomin VH. Structural requirements of Holothuria floridana fucosylated chondroitin sulfate oligosaccharides in anti-SARS-CoV-2 and anticoagulant activities. PLoS One 2023; 18:e0285539. [PMID: 37167245 PMCID: PMC10174540 DOI: 10.1371/journal.pone.0285539] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2023] [Accepted: 04/25/2023] [Indexed: 05/13/2023] Open
Abstract
Fucosylated chondroitin sulfate (FucCS) is a unique glycosaminoglycan found primarily in sea cucumbers. This marine sulfated glycan is composed of a chondroitin sulfate backbone decorated with fucosyl branches attached to the glucuronic acid. FucCS exhibits potential biological actions including inhibition of blood clotting and severe acute respiratory syndrome coronavirus (SARS-CoV-2) infection. These biological effects have been attributed to certain structural features, including molecular weight (MW), and/or those related to fucosylation, such as degrees of fucosyl branches, sulfation patterns and contents. In a previous work, we were able to generate oligosaccharides of the FucCS from Pentacta pygmaea (PpFucCS) with reduced anticoagulant effect but still retaining significant anti-SARS-CoV-2 activity against the delta strain. In this work, we extended our study to the FucCS extracted from the species Holothuria floridana (HfFucCS). The oligosaccharides were prepared by free-radical depolymerization of the HfFucCS via copper-based Fenton reaction. One-dimensional 1H nuclear magnetic resonance spectra were employed in structural analysis. Activated partial thromboplastin time and assays using protease (factors Xa and IIa) and serine protease inhibitors (antithrombin, and heparin cofactor II) in the presence of the sulfated carbohydrates were used to monitor anticoagulation. Anti-SARS-CoV-2 effects were measured using the concentration-response inhibitory curves of HEK-293T-human angiotensin-converting enzyme-2 cells infected with a baculovirus pseudotyped SARS-CoV-2 wild-type and delta variant spike (S)-proteins. Furthermore, the cytotoxicity of native HfFucCS and its oligosaccharides was also assessed. Like for PpFucCS, we were able to generate a HfFucCS oligosaccharide fraction devoid of high anticoagulant effect but still retaining considerable anti-SARS-CoV-2 actions against both variants. However, compared to the oligosaccharide fraction derived from PpFucCS, the average MW of the shortest active HfFucCS oligosaccharide fraction was significantly lower. This finding suggests that the specific structural feature in HfFucCS, the branching 3,4-di-sulfated fucoses together with the backbone 4,6-di-sulfated N-acetylgalactosamines, is relevant for the anti-SARS-CoV-2 activity of FucCS molecules.
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Affiliation(s)
- Marwa Farrag
- Department of BioMolecular Sciences, University of Mississippi, Oxford, Mississippi, United States of America
- Department of Pharmacognosy, Faculty of Pharmacy, Assiut University, Assiut, Egypt
| | - Rohini Dwivedi
- Department of BioMolecular Sciences, University of Mississippi, Oxford, Mississippi, United States of America
| | - Poonam Sharma
- Center for Immunology and Microbial Research, Department of Cell and Molecular Biology, University of Mississippi Medical Center, Jackson, Mississippi, United States of America
| | - Deepak Kumar
- Center for Immunology and Microbial Research, Department of Cell and Molecular Biology, University of Mississippi Medical Center, Jackson, Mississippi, United States of America
| | - Ritesh Tandon
- Department of BioMolecular Sciences, University of Mississippi, Oxford, Mississippi, United States of America
- Center for Immunology and Microbial Research, Department of Cell and Molecular Biology, University of Mississippi Medical Center, Jackson, Mississippi, United States of America
- Department of Medicine, University of Mississippi Medical Center, Jackson, Mississippi, United States of America
| | - Vitor H. Pomin
- Department of BioMolecular Sciences, University of Mississippi, Oxford, Mississippi, United States of America
- Research Institute of Pharmaceutical Sciences, School of Pharmacy, University of Mississippi, Oxford, MS, United States of America
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7
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Bono A, Lauria A, La Monica G, Alamia F, Mingoia F, Martorana A. In Silico Design of New Dual Inhibitors of SARS-CoV-2 M PRO through Ligand- and Structure-Based Methods. Int J Mol Sci 2023; 24:ijms24098377. [PMID: 37176082 PMCID: PMC10179319 DOI: 10.3390/ijms24098377] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2023] [Revised: 04/28/2023] [Accepted: 05/05/2023] [Indexed: 05/15/2023] Open
Abstract
The viral main protease is one of the most attractive targets among all key enzymes involved in the life cycle of SARS-CoV-2. Considering its mechanism of action, both the catalytic and dimerization regions could represent crucial sites for modulating its activity. Dual-binding the SARS-CoV-2 main protease inhibitors could arrest the replication process of the virus by simultaneously preventing dimerization and proteolytic activity. To this aim, in the present work, we identified two series' of small molecules with a significant affinity for SARS-CoV-2 MPRO, by a hybrid virtual screening protocol, combining ligand- and structure-based approaches with multivariate statistical analysis. The Biotarget Predictor Tool was used to filter a large in-house structural database and select a set of benzo[b]thiophene and benzo[b]furan derivatives. ADME properties were investigated, and induced fit docking studies were performed to confirm the DRUDIT prediction. Principal component analysis and docking protocol at the SARS-CoV-2 MPRO dimerization site enable the identification of compounds 1b,c,i,l and 2i,l as promising drug molecules, showing favorable dual binding site affinity on SARS-CoV-2 MPRO.
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Affiliation(s)
- Alessia Bono
- Dipartimento di Scienze e Tecnologie Biologiche, Chimiche e Farmaceutiche "STEBICEF", University of Palermo, Viale delle Scienze, Ed. 17, 90128 Palermo, Italy
| | - Antonino Lauria
- Dipartimento di Scienze e Tecnologie Biologiche, Chimiche e Farmaceutiche "STEBICEF", University of Palermo, Viale delle Scienze, Ed. 17, 90128 Palermo, Italy
| | - Gabriele La Monica
- Dipartimento di Scienze e Tecnologie Biologiche, Chimiche e Farmaceutiche "STEBICEF", University of Palermo, Viale delle Scienze, Ed. 17, 90128 Palermo, Italy
| | - Federica Alamia
- Dipartimento di Scienze e Tecnologie Biologiche, Chimiche e Farmaceutiche "STEBICEF", University of Palermo, Viale delle Scienze, Ed. 17, 90128 Palermo, Italy
| | - Francesco Mingoia
- Istituto per lo Studio dei Materiali Nanostrutturati (ISMN), Consiglio Nazionale delle Ricerche (CNR), Via Ugo La Malfa, 153, 90146 Palermo, Italy
| | - Annamaria Martorana
- Dipartimento di Scienze e Tecnologie Biologiche, Chimiche e Farmaceutiche "STEBICEF", University of Palermo, Viale delle Scienze, Ed. 17, 90128 Palermo, Italy
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8
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Atari N, Erster O, Shteinberg YH, Asraf H, Giat E, Mandelboim M, Goldstein I. Proof-of-concept for effective antiviral activity of an in silico designed decoy synthetic mRNA against SARS-CoV-2 in the Vero E6 cell-based infection model. Front Microbiol 2023; 14:1113697. [PMID: 37152730 PMCID: PMC10157240 DOI: 10.3389/fmicb.2023.1113697] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2022] [Accepted: 04/03/2023] [Indexed: 05/09/2023] Open
Abstract
The positive-sense single-stranded (ss) RNA viruses of the Betacoronavirus (beta-CoV) genus can spillover from mammals to humans and are an ongoing threat to global health and commerce, as demonstrated by the current zoonotic pandemic of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Current anti-viral strategies focus on vaccination or targeting key viral proteins with antibodies and drugs. However, the ongoing evolution of new variants that evade vaccination or may become drug-resistant is a major challenge. Thus, antiviral compounds that circumvent these obstacles are needed. Here we describe an innovative antiviral modality based on in silico designed fully synthetic mRNA that is replication incompetent in uninfected cells (termed herein PSCT: parasitic anti-SARS-CoV-2 transcript). The PSCT sequence was engineered to include key untranslated cis-acting regulatory RNA elements of the SARS-CoV-2 genome, so as to effectively compete for replication and packaging with the standard viral genome. Using the Vero E6 cell-culture based SARS-CoV-2 infection model, we determined that the intracellular delivery of liposome-encapsulated PSCT at 1 hour post infection significantly reduced intercellular SARS-CoV-2 replication and release into the extracellular milieu as compared to mock treatment. In summary, our findings are a proof-of-concept for the therapeutic feasibility of in silico designed mRNA compounds formulated to hinder the replication and packaging of ssRNA viruses sharing a comparable genomic-structure with beta-CoVs.
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Affiliation(s)
- Nofar Atari
- Central Virology Laboratory, Public Health Services, Ministry of Health, Sheba Medical Center, Tel HaShomer, Israel
- Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Oran Erster
- Central Virology Laboratory, Public Health Services, Ministry of Health, Sheba Medical Center, Tel HaShomer, Israel
| | | | - Hadar Asraf
- Central Virology Laboratory, Public Health Services, Ministry of Health, Sheba Medical Center, Tel HaShomer, Israel
| | - Eitan Giat
- Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
- The Department of Medicine, Sheba Medical Center, Ramat Gan, Israel
| | - Michal Mandelboim
- Central Virology Laboratory, Public Health Services, Ministry of Health, Sheba Medical Center, Tel HaShomer, Israel
- The Department of Medicine, Sheba Medical Center, Ramat Gan, Israel
| | - Itamar Goldstein
- Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
- The Department of Medicine, Sheba Medical Center, Ramat Gan, Israel
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9
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Schuller M, Zarganes-Tzitzikas T, Bennett J, De Cesco S, Fearon D, von Delft F, Fedorov O, Brennan PE, Ahel I. Discovery and Development Strategies for SARS-CoV-2 NSP3 Macrodomain Inhibitors. Pathogens 2023; 12:324. [PMID: 36839595 PMCID: PMC9965906 DOI: 10.3390/pathogens12020324] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2023] [Revised: 02/03/2023] [Accepted: 02/10/2023] [Indexed: 02/17/2023] Open
Abstract
The worldwide public health and socioeconomic consequences caused by the COVID-19 pandemic highlight the importance of increasing preparedness for viral disease outbreaks by providing rapid disease prevention and treatment strategies. The NSP3 macrodomain of coronaviruses including SARS-CoV-2 is among the viral protein repertoire that was identified as a potential target for the development of antiviral agents, due to its critical role in viral replication and consequent pathogenicity in the host. By combining virtual and biophysical screening efforts, we discovered several experimental small molecules and FDA-approved drugs as inhibitors of the NSP3 macrodomain. Analogue characterisation of the hit matter and crystallographic studies confirming binding modes, including that of the antibiotic compound aztreonam, to the active site of the macrodomain provide valuable structure-activity relationship information that support current approaches and open up new avenues for NSP3 macrodomain inhibitor development.
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Affiliation(s)
- Marion Schuller
- Sir William Dunn School of Pathology, University of Oxford, Oxford OX1 3RE, UK
| | | | - James Bennett
- Centre for Medicines Discovery, University of Oxford, Headington OX3 7DQ, UK
| | - Stephane De Cesco
- Centre for Medicines Discovery, University of Oxford, Headington OX3 7DQ, UK
| | - Daren Fearon
- Diamond Light Source Ltd., Harwell Science and Innovation Campus, Didcot OX11 0DE, UK
- Research Complex at Harwell, Harwell Science and Innovation Campus, Didcot OX11 0FA, UK
| | - Frank von Delft
- Centre for Medicines Discovery, University of Oxford, Headington OX3 7DQ, UK
- Diamond Light Source Ltd., Harwell Science and Innovation Campus, Didcot OX11 0DE, UK
- Research Complex at Harwell, Harwell Science and Innovation Campus, Didcot OX11 0FA, UK
- Structural Genomics Consortium, University of Oxford, Headington OX3 7DQ, UK
- Department of Biochemistry, University of Johannesburg, Auckland Park, Johannesburg 2006, South Africa
| | - Oleg Fedorov
- Centre for Medicines Discovery, University of Oxford, Headington OX3 7DQ, UK
| | - Paul E. Brennan
- Centre for Medicines Discovery, University of Oxford, Headington OX3 7DQ, UK
| | - Ivan Ahel
- Sir William Dunn School of Pathology, University of Oxford, Oxford OX1 3RE, UK
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Janeena A, Jayaraman N, Shanmugam G, Easwaramoorthi S, Ayyadurai N. Electrochemical Response of Redox Amino Acid Encoded Fluorescence Protein for Hydroxychloroquine Sensing. Appl Biochem Biotechnol 2023; 195:992-1013. [PMID: 36260248 PMCID: PMC9581447 DOI: 10.1007/s12010-022-04142-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/28/2022] [Indexed: 01/24/2023]
Abstract
The sudden rise in the demand has led to large-scale production of hydroxychloroquine (HCQ) in the global market for various diseases such as malaria, rheumatic arthritis, and systemic lupus erythematous and prophylactic treatment of early SARS-CoV-2 outbreak. Thorough monitoring of HCQ intake patients is in high demand; hence, we have developed a redox amino acid encoded fluorescent protein-based electrochemical biosensor for sensitive and selective detection of HCQ. This electrochemical biosensor is generated based on the two-electron transfer process between redox amino acid (3,4-dihydroxy-L-phenylalanine, DOPA) encoded bio-redox protein and the HCQ forms the conjugate. The DOPA residue in the bio-redox protein specifically binds with HCQ, thereby producing a remarkable electrochemical response on the glassy carbon electrode. Experimental results show that the developed biosensor selectively and sensitively detects the HCQ in spiked urine samples. The reagent-free bio-redox capacitor detects HCQ in the range of 90 nM to 4.4 µM in a solution with a detection limit of 58 nM, signal to noise ratio of 3:1, and strong anti-interference ability. Real-time screening, quantification, and relative mean recoveries of HCQ on spiked urine samples were monitored through electron shuttling using bio-redox protein and were found to be 97 to 101%. Overall, the developed bio-redox protein-based sensor has specificity, selectivity, reproducibility, and sensitivity making it potentially attractive for the sensing of HCQ and also applicable to clinical research.
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Affiliation(s)
- Asuma Janeena
- Biotechnology and Biochemistry, Council of Scientific and Industrial Research (CSIR)-Central Leather Research Institute, Chennai, India
- Academy of Scientific and Industrial Research (AcSIR), 201002, Ghaziabad, India
| | - Narayanan Jayaraman
- Inorganic and Physical Chemistry, Council of Scientific and Industrial Research (CSIR)-Central Leather Research Institute, Chennai, India
| | - Ganesh Shanmugam
- Academy of Scientific and Industrial Research (AcSIR), 201002, Ghaziabad, India
- Organic and Bio-Organic Chemistry, Council of Scientific and Industrial Research (CSIR)-Central Leather Research Institute, Chennai, India
| | - Shanmugam Easwaramoorthi
- Academy of Scientific and Industrial Research (AcSIR), 201002, Ghaziabad, India.
- Inorganic and Physical Chemistry, Council of Scientific and Industrial Research (CSIR)-Central Leather Research Institute, Chennai, India.
| | - Niraikulam Ayyadurai
- Biotechnology and Biochemistry, Council of Scientific and Industrial Research (CSIR)-Central Leather Research Institute, Chennai, India.
- Academy of Scientific and Industrial Research (AcSIR), 201002, Ghaziabad, India.
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11
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Khatri R, Siddqui G, Sadhu S, Maithil V, Vishwakarma P, Lohiya B, Goswami A, Ahmed S, Awasthi A, Samal S. Intrinsic D614G and P681R/H mutations in SARS-CoV-2 VoCs Alpha, Delta, Omicron and viruses with D614G plus key signature mutations in spike protein alters fusogenicity and infectivity. Med Microbiol Immunol 2023; 212:103-122. [PMID: 36583790 PMCID: PMC9801140 DOI: 10.1007/s00430-022-00760-7] [Citation(s) in RCA: 22] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2022] [Accepted: 12/03/2022] [Indexed: 12/31/2022]
Abstract
The SARS-CoV-2 virus has been rapidly evolving over the time and the genetic variation has led to the generation of Variants of Concerns (VoC), which have shown increased fitness. These VoC viruses contain the key mutations in the spike protein which have allowed better survival and evasion of host defense mechanisms. The D614G mutation in the spike domain is found in the majority of VoC; additionally, the P681R/H mutation at the S1/S2 furin cleavage site junction is also found to be highly conserved in major VoCs; Alpha, Delta, Omicron, and its' current variants. The impact of these genetic alterations of the SARS-CoV-2 VoCs on the host cell entry, transmissibility, and infectivity has not been clearly identified. In our study, Delta and D614G + P681R synthetic double mutant pseudoviruses showed a significant increase in the cell entry, cell-to-cell fusion and infectivity. In contrast, the Omicron and P681H synthetic single mutant pseudoviruses showed TMPRSS2 independent cell entry, less fusion and infectivity as compared to Delta and D614G + P681R double mutants. Addition of exogenous trypsin further enhanced fusion in Delta viruses as compared to Omicron. Furthermore, Delta viruses showed susceptibility to both E64d and Camostat mesylate inhibitors suggesting, that the Delta virus could exploit both endosomal and TMPRSS2 dependent entry pathways as compared to the Omicron virus. Taken together, these results indicate that the D614G and P681R/H mutations in the spike protein are pivotal which might be favoring the VoC replication in different host compartments, and thus allowing a balance of mutation vs selection for better long-term adaptation.
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Affiliation(s)
- Ritika Khatri
- Translational Health Science and Technology Institute, NCR Biotech Science Cluster, Faridabad, Haryana, 121001, India
| | - Gazala Siddqui
- Translational Health Science and Technology Institute, NCR Biotech Science Cluster, Faridabad, Haryana, 121001, India
| | - Srikanth Sadhu
- Translational Health Science and Technology Institute, NCR Biotech Science Cluster, Faridabad, Haryana, 121001, India
- Immunobiology and Immunology Core Laboratory, Translational Health Science and Technology Institute, NCR Biotech Science Cluster, Faridabad, Haryana, 121001, India
| | - Vikas Maithil
- Translational Health Science and Technology Institute, NCR Biotech Science Cluster, Faridabad, Haryana, 121001, India
| | - Preeti Vishwakarma
- Translational Health Science and Technology Institute, NCR Biotech Science Cluster, Faridabad, Haryana, 121001, India
| | - Bharat Lohiya
- Translational Health Science and Technology Institute, NCR Biotech Science Cluster, Faridabad, Haryana, 121001, India
| | - Abhishek Goswami
- Translational Health Science and Technology Institute, NCR Biotech Science Cluster, Faridabad, Haryana, 121001, India
| | - Shubbir Ahmed
- Centralized Core Research Facility (CCRF), All India Institute of Medical Science (AIIMS), Delhi, India
| | - Amit Awasthi
- Translational Health Science and Technology Institute, NCR Biotech Science Cluster, Faridabad, Haryana, 121001, India
- Immunobiology and Immunology Core Laboratory, Translational Health Science and Technology Institute, NCR Biotech Science Cluster, Faridabad, Haryana, 121001, India
| | - Sweety Samal
- Translational Health Science and Technology Institute, NCR Biotech Science Cluster, Faridabad, Haryana, 121001, India.
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12
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Dwivedi R, Sharma P, Eilts F, Zhang F, Linhardt RJ, Tandon R, Pomin VH. Anti-SARS-CoV-2 and anticoagulant properties of Pentacta pygmaea fucosylated chondroitin sulfate depend on high molecular weight structures. Glycobiology 2023; 33:75-85. [PMID: 36136750 PMCID: PMC9829039 DOI: 10.1093/glycob/cwac063] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2022] [Revised: 09/12/2022] [Accepted: 09/12/2022] [Indexed: 01/28/2023] Open
Abstract
Fucosylated chondroitin sulfate (FucCS) is a unique marine glycosaminoglycan that exhibits diverse biological functions, including antiviral and anticoagulant activity. In previous work, the FucCS derived from Pentacta pygmaea (PpFucCS) showed moderate anticoagulant effect but high inhibitory activity against the Wuhan strain of severe acute respiratory syndrome coronavirus (SARS-CoV-2). In this study, we perform free-radical depolymerization of PpFucCS by the copper-based Fenton method to generate low molecular weight (MW) oligosaccharides. PpFucCS oligosaccharides were structurally analyzed by 1H nuclear magnetic resonance spectroscopy and were used to conduct structure-activity relationship studies regarding their effects against SARS-CoV-2 and clotting. Anticoagulant properties were measured by activated partial thromboplastin time, protease (factors Xa and IIa) inhibition by serine protease inhibitors (antithrombin [AT] and heparin cofactor II [HCII]), and competitive surface plasmon resonance (SPR) assay using AT, HCII, and IIa. Anti-SARS-CoV-2 properties were measured by the concentration-response inhibitory curves of HEK-293T-human angiotensin-converting enzyme-2 cells infected with a baculovirus pseudotyped SARS-CoV-2 Delta variant spike (S)-protein and competitive SPR assays using multiple S-proteins (Wuhan, N501Y [Alpha], K417T/E484K/N501Y [Gamma], L542R [Delta], and Omicron [BA.2 subvariant]). Cytotoxicity of native PpFucCS and oligosaccharides was also assessed. The PpFucCS-derived oligosaccharide fraction of the highest MW showed great anti-SARS-CoV-2 Delta activity and reduced anticoagulant properties. Results have indicated no cytotoxicity and MW dependency on both anti-SARS-CoV-2 and anticoagulant effects of PpFucCS, as both actions were reduced accordingly to the MW decrease of PpFucCS. Our results demonstrate that the high-MW structures of PpFucCS is a key structural element to achieve the maximal anti-SARS-CoV-2 and anticoagulant effects.
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Affiliation(s)
- Rohini Dwivedi
- Department of BioMolecular Sciences, University of Mississippi, Oxford, Mississippi 38677, United States
| | - Poonam Sharma
- Center for Immunology and Microbial Research, Department of Cell Biology, University of Mississippi Medical Center, Jackson, MS 39216, United States
| | - Friederike Eilts
- Center for Biotechnology and Interdisciplinary Studies, Rensselaer Polytechnic Institute, Troy, NY 12180, United States
- Institute of Bioprocess Engineering and Pharmaceutical Technology, University of Applied Sciences Mittelhessen (THM), Giessen 35390, Germany
| | - Fuming Zhang
- Center for Biotechnology and Interdisciplinary Studies, Rensselaer Polytechnic Institute, Troy, NY 12180, United States
| | - Robert J Linhardt
- Center for Biotechnology and Interdisciplinary Studies, Rensselaer Polytechnic Institute, Troy, NY 12180, United States
| | - Ritesh Tandon
- Department of BioMolecular Sciences, University of Mississippi, Oxford, Mississippi 38677, United States
- Center for Immunology and Microbial Research, Department of Cell Biology, University of Mississippi Medical Center, Jackson, MS 39216, United States
- Department of Medicine, University of Mississippi Medical Center, Jackson, MS 39216, United States
| | - Vitor H Pomin
- Department of BioMolecular Sciences, University of Mississippi, Oxford, Mississippi 38677, United States
- School of Pharmacy, Research Institute of Pharmaceutical Sciences, University of Mississippi, Oxford, MS 38677, United States
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Khwaza V, Buyana B, Nqoro X, Peter S, Mbese Z, Feketshane Z, Alven S, Aderibigbe BA. Strategies for delivery of antiviral agents. VIRAL INFECTIONS AND ANTIVIRAL THERAPIES 2023:407-492. [DOI: 10.1016/b978-0-323-91814-5.00018-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/06/2025]
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14
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Bibi N, Farid A, Gul S, Ali J, Amin F, Kalthiya U, Hupp T. Drug repositioning against COVID-19: a first line treatment. J Biomol Struct Dyn 2022; 40:12812-12826. [PMID: 34519259 PMCID: PMC8442756 DOI: 10.1080/07391102.2021.1977698] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
COVID-19 disease caused by the SARS-CoV-2 virus has shaken our health and wealth foundations. Although COVID-19 vaccines will become available allowing for attenuation of disease progression rates, distribution of vaccines can create other challenges and delays. Hence repurposed drugs against SARS-CoV-2 can be an attractive parallel strategy that can be integrated into routine clinical practice even in poorly-resourced countries. The present study was designed using knowledge of viral pathogenesis and pharmacodynamics of broad-spectrum antiviral agents (BSAAs). We carried out the virtual screening of BSAAs against the SARS-CoV-2 spike glycoprotein, RNA dependent RNA polymerase (RdRp), the main protease (Mpro) and the helicase enzyme of SARS-CoV-2. Imatinib (a tyrosine kinase inhibitor), Suramin (an anti-parasitic), Glycyrrhizin (an anti-inflammatory) and Bromocriptine (a dopamine agonist) showed higher binding affinity to multiple targets. Further through molecular dynamics simulation, critical conformational changes in the target protein molecules were revealed upon drug binding which illustrates the favorable binding conformations of antiviral drugs against SARS-CoV-2 target proteins. The resulting drugs from the present study in combination and in cocktails from the arsenal of existing drugs could reduce the translational distance and could offer substantial clinical benefit to decrease the burden of COVID-19 illness. This also creates a roadmap for subsequent viral diseases that emerge.Communicated by Ramaswamy H. Sarma.
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Affiliation(s)
- Nousheen Bibi
- Department of Bioinformatics, Shaheed Benazir Bhutto Women University, Peshawar, Pakistan,CONTACT Nousheen Bibi ; Department of Bioinformatics, Shaheed Benazir Bhutto Women University, Peshawar, Pakistan
| | - Ayesha Farid
- Department of Bioinformatics, Shaheed Benazir Bhutto Women University, Peshawar, Pakistan
| | - Sana Gul
- Department of Bioinformatics, Shaheed Benazir Bhutto Women University, Peshawar, Pakistan
| | - Johar Ali
- Center for Genomics Sciences RMI, Peshawar, Pakistan
| | - Farhat Amin
- Department of Bioinformatics, Shaheed Benazir Bhutto Women University, Peshawar, Pakistan
| | - Umesh Kalthiya
- International Center for Cancer Vaccine Science, Gdańsk, Poland
| | - Ted Hupp
- International Center for Cancer Vaccine Science, Gdańsk, Poland,Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK
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15
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Bajrai LH, Faizo AA, Alkhaldy AA, Dwivedi VD, Azhar EI. Repositioning of anti-dengue compounds against SARS-CoV-2 as viral polyprotein processing inhibitor. PLoS One 2022; 17:e0277328. [PMID: 36383621 PMCID: PMC9668197 DOI: 10.1371/journal.pone.0277328] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2022] [Accepted: 10/24/2022] [Indexed: 11/17/2022] Open
Abstract
A therapy for COVID-19 (Coronavirus Disease 19) caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) remains elusive due to the lack of an effective antiviral therapeutic molecule. The SARS-CoV-2 main protease (Mpro), which plays a vital role in the viral life cycle, is one of the most studied and validated drug targets. In Several prior studies, numerous possible chemical entities were proposed as potential Mpro inhibitors; however, most failed at various stages of drug discovery. Repositioning of existing antiviral compounds accelerates the discovery and development of potent therapeutic molecules. Hence, this study examines the applicability of anti-dengue compounds against the substrate binding site of Mpro for disrupting its polyprotein processing mechanism. An in-silico structure-based virtual screening approach is applied to screen 330 experimentally validated anti-dengue compounds to determine their affinity to the substrate binding site of Mpro. This study identified the top five compounds (CHEMBL1940602, CHEMBL2036486, CHEMBL3628485, CHEMBL200972, CHEMBL2036488) that showed a high affinity to Mpro with a docking score > -10.0 kcal/mol. The best-docked pose of these compounds with Mpro was subjected to 100 ns molecular dynamic (MD) simulation followed by MM/GBSA binding energy. This showed the maximum stability and comparable ΔG binding energy against the reference compound (X77 inhibitor). Overall, we repurposed the reported anti-dengue compounds against SARS-CoV-2-Mpro to impede its polyprotein processing for inhibiting SARS-CoV-2 infection.
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Affiliation(s)
- Leena H. Bajrai
- Special Infectious Agents Unit – BSL3, King Fahd Medical Research Center, King Abdulaziz University, Jeddah, Saudi Arabia
- Biochemistry Department, Faculty of Sciences, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Arwa A. Faizo
- Special Infectious Agents Unit – BSL3, King Fahd Medical Research Center, King Abdulaziz University, Jeddah, Saudi Arabia
- Department of Medical Laboratory Sciences, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Areej A. Alkhaldy
- Special Infectious Agents Unit – BSL3, King Fahd Medical Research Center, King Abdulaziz University, Jeddah, Saudi Arabia
- Clinical Nutrition Department, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Vivek Dhar Dwivedi
- Center for Bioinformatics, Computational and Systems Biology, Pathfinder Research and Training Foundation, Greater Noida, India
- Bioinformatics Research Division, Quanta Calculus, Greater Noida, India
| | - Esam I. Azhar
- Special Infectious Agents Unit – BSL3, King Fahd Medical Research Center, King Abdulaziz University, Jeddah, Saudi Arabia
- Department of Medical Laboratory Sciences, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah, Saudi Arabia
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16
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Nabati F, kamyabiamineh A, Kosari R, Ghasemi F, Seyedebrahimi S, Mohammadi S, Moradi M. Virtual screening based on the structure of more than 105 compounds against four key proteins of SARS-CoV-2: MPro, SRBD, RdRp, and PLpro. INFORMATICS IN MEDICINE UNLOCKED 2022; 35:101134. [PMID: 36406927 PMCID: PMC9652154 DOI: 10.1016/j.imu.2022.101134] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2022] [Revised: 11/11/2022] [Accepted: 11/11/2022] [Indexed: 11/15/2022] Open
Abstract
Background SARS-CoV-2 initially originated in Wuhan (China) around December 2019, and spread all over the world. Currently, WHO (Word Health Organization) has licensed several vaccines for this viral infection. However, not everyone can be vaccinated. People with underlying health conditions that weaken their immune systems or those with severe allergies to some vaccine components, may not be able to be vaccinated. Moreover, no vaccination is 100% safe, and the emergence of new SARS-CoV-2 mutations may reduce the efficacy of immunizations. Therefore, it is urgent to develop effective drugs to protect people against this virus. Material and method We performed structure-based virtual screening (SBVS) of a library that was built from ChemDiv and PubChem databases against four SARS-CoV-2 target proteins: S-protein (spike), main protease (MPro), RNA-dependent RNA polymerase, and PLpro. A virtual screening study was performed using PyRx and AutoDock tools. Results Our results suggest that twenty-five top-ranked drugs with the highest energy binding as the potential inhibitors against four SARS-CoV-2 targets, relative to the reference molecules. Based on the energy binding, we suggest that these compounds could be used to produce effective anti-viral drugs against SARS-CoV-2. Conclusion The discovery of novel compounds for COVID-19 using computer-aided drug discovery tools requires knowledge of the structure of coronavirus and various target proteins of the virus. These compounds should be further assessed in experimental assays and clinical trials to validate their actual activity against the disease. These findings may contribute to the drug design studies against COVID-19.
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17
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Hardy S, Choo YM, Hamann M, Cray J. Manzamine-A Alters In Vitro Calvarial Osteoblast Function. Mar Drugs 2022; 20:647. [PMID: 36286470 PMCID: PMC9604769 DOI: 10.3390/md20100647] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2022] [Revised: 10/07/2022] [Accepted: 10/14/2022] [Indexed: 11/17/2022] Open
Abstract
Manzamine-A is a marine-derived alkaloid which has anti-viral and anti-proliferative properties and is currently being investigated for its efficacy in the treatment of certain viruses (malaria, herpes, HIV-1) and cancers (breast, cervical, colorectal). Manzamine-A has been found to exert effects via modulation of SIX1 gene expression, a gene critical to craniofacial development via the WNT, NOTCH, and PI3K/AKT pathways. To date little work has focused on Manzamine-A and how its use may affect bone. We hypothesize that Manzamine-A, through SIX1, alters bone cell activity. Here, we assessed the effects of Manzamine-A on cells that are responsible for the generation of bone, pre-osteoblasts and osteoblasts. PCR, qrtPCR, MTS cell viability, Caspase 3/7, and functional assays were used to test the effects of Manzamine-A on these cells. Our data suggests Six1 is highly expressed in osteoblasts and their progenitors. Further, osteoblast progenitors and osteoblasts exhibit great sensitivity to Manzamine-A treatment exhibited by a significant decrease in cell viability, increase in cellular apoptosis, and decrease in alkaline phosphatase activity. In silico binding experiment showed that manzamine A potential as an inhibitor of cell proliferation and survival proteins, i.e., Iκb, JAK2, AKT, PKC, FAK, and Bcl-2. Overall, our data suggests Manzamine-A may have great effects on bone health overall and may disrupt skeletal development, homeostasis, and repair.
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Affiliation(s)
- Samantha Hardy
- Department of Biomedical Education and Anatomy, College of Medicine, The Ohio State University, Columbus, OH 43210, USA
| | - Yeun-Mun Choo
- Chemistry Department, Faculty of Science, University of Malaya, Kuala Lumpur 50603, Malaysia
| | - Mark Hamann
- Departments of Drug Discovery and Biomedical Sciences and Public Health, Colleges of Pharmacy and Medicine, Medical University of South Carolina, Charleston, SC 29425, USA
| | - James Cray
- Department of Biomedical Education and Anatomy, College of Medicine, The Ohio State University, Columbus, OH 43210, USA
- Division of Biosciences, The Ohio State College of Dentistry, Columbus, OH 43210, USA
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Development of a database of RNA helicase inhibitors (VHIMDB) of pathogenic viruses and in silico screening for the potential drug molecules. THE EUROBIOTECH JOURNAL 2022. [DOI: 10.2478/ebtj-2022-0012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Abstract
The pathogenic RNA virus that infects human beings contains the RNA helicase enzyme, responsible for the replication of the viral genome. The enzyme is used as a suitable target against which the drug molecule acts. Therefore, the identification and proposal the novel compounds that can be targeted toward the helicase enzymes to stop the functioning of the enzyme is desirable. Although many viral helicase inhibitor molecules have been identified, still yet no unique database is available for these compounds. This research work envisages developing a curated database of RNA helicase inhibitors. The database contains in total of 353 entries that are computationally predicted and experimentally verified RNA helicase inhibitors. The database contains information like compound name, chemical properties, chemical format, and name of the target virus to which it acts against it with a user-friendly menu-driven search engine. Presently, the database is freely available at: https://vhimdb.rsatpathy.in/. Further, in silico screening of the whole database by drug-likeness and toxicity resulted in 14 potential drug molecules. The selected molecules were analyzed for their effectiveness in binding by using molecular docking score and interaction with the helicase enzymes of three categories of pathogenic viruses (SARS-CoV-2, SARS-CoV, and MERS-CoV).
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19
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Hamdy R, Mostafa A, Abo Shama NM, Soliman SSM, Fayed B. Comparative evaluation of flavonoids reveals the superiority and promising inhibition activity of silibinin against SARS-CoV-2. Phytother Res 2022; 36:2921-2939. [PMID: 35596627 PMCID: PMC9347486 DOI: 10.1002/ptr.7486] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2021] [Revised: 03/19/2022] [Accepted: 04/22/2022] [Indexed: 01/08/2023]
Abstract
Flavonoids are phenolic compounds naturally found in plants and commonly consumed in diets. Herein, flavonoids were sequentially evaluated by a comparative in silico study associated with systematic literature search. This was followed by an in vitro study and enzyme inhibition assays against vital SARS-CoV-2 proteins including spike (S) protein, main protease (Mpro ), RNA-dependent RNA-polymerase (RdRp), and human transmembrane serine protease (TMPRSS2). The results obtained revealed 10 flavonoids with potential antiviral activity. Out of them, silibinin showed promising selectivity index against SARS-CoV-2 in vitro. Screening against S protein discloses the highest inhibition activity of silibinin. Mapping the activity of silibinin indicated its excellent binding inhibition activity against SARS-CoV-2 S protein, Mpro and RdRP at IC50 0.029, 0.021, and 0.042 μM, respectively, while it showed no inhibition activity against TMPRSS2 at its IC50(SARS-CoV-2) . Silibinin was tested safe on human mammalian cells at >7-fold its IC50(SARS-CoV-2) . Additionally, silibinin exhibited >90% virucidal activity at 0.031 μM. Comparative molecular docking (MD) showed that silibinin possesses the highest binding affinity to S protein and RdRP at -7.78 and -7.15 kcal/mol, respectively. MDs showed that silibinin exhibited stable interaction with key amino acids of SARS-CoV-2 targets. Collectively, silibinin, an FDA-approved drug, can significantly interfere with SARS-CoV-2 entry and replication through multi-targeting activity.
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Affiliation(s)
- Rania Hamdy
- Research Institute for Medical and Health SciencesUniversity of SharjahSharjahUnited Arab Emirates
- Faculty of PharmacyZagazig UniversityZagazigEgypt
| | - Ahmed Mostafa
- Center of Scientific Excellence for Influenza VirusesNational Research CentreGizaEgypt
| | - Noura M. Abo Shama
- Center of Scientific Excellence for Influenza VirusesNational Research CentreGizaEgypt
| | - Sameh S. M. Soliman
- Research Institute for Medical and Health SciencesUniversity of SharjahSharjahUnited Arab Emirates
- College of PharmacyUniversity of SharjahSharjahUnited Arab Emirates
| | - Bahgat Fayed
- Research Institute for Medical and Health SciencesUniversity of SharjahSharjahUnited Arab Emirates
- Chemistry of Natural and Microbial Product DepartmentNational Research CentreCairoEgypt
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20
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Debnath SK, Debnath M, Srivastava R, Omri A. Drugs repurposing for SARS-CoV-2: new insight of COVID-19 druggability. Expert Rev Anti Infect Ther 2022; 20:1187-1204. [PMID: 35615888 DOI: 10.1080/14787210.2022.2082944] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
INTRODUCTION The ongoing epidemic of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) creates a massive panic worldwide due to the absence of effective medicines. Developing a new drug or vaccine is time-consuming to pass safety and efficacy testing. Therefore, repurposing drugs have been introduced to treat COVID-19 until effective drugs are developed. AREA COVERED A detailed search of repurposing drugs against SARS-CoV-2 was carried out using the PubMed database, focusing on articles published 2020 years onward. A different class of drugs has been described in this article to target hosts and viruses. Based on the previous pandemic experience of SARS-CoV and MERS, several antiviral and antimalarial drugs are discussed here. This review covers the failure of some repurposed drugs that showed promising activity in the earlier CoV-pandemic but were found ineffective against SARS-CoV-2. All these discussions demand a successful drug development strategy for screening and identifying an effective drug for better management of COVID-19. The drug development strategies described here will serve a new scope of research for academicians and researchers. EXPERT OPINION Repurposed drugs have been used since COVID-19 to eradicate disease propagation. Drugs found effective for MERS and SARS may not be effective against SARS-CoV-2. Drug libraries and artificial intelligence are helpful tools to screen and identify different molecules targeting viruses or hosts.
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Affiliation(s)
- Sujit Kumar Debnath
- Department of Biosciences and Bioengineering, Indian Institute of Technology Bombay, Mumbai, India
| | - Monalisha Debnath
- Department of Biosciences and Bioengineering, Indian Institute of Technology Bombay, Mumbai, India
| | - Rohit Srivastava
- Department of Biosciences and Bioengineering, Indian Institute of Technology Bombay, Mumbai, India
| | - Abdelwahab Omri
- Department of Chemistry and Biochemistry, The Novel Drug & Vaccine Delivery Systems Facility, Laurentian University, Sudbury, Canada
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Xu T, Xu M, Zhu W, Chen CZ, Zhang Q, Zheng W, Huang R. Efficient Identification of Anti-SARS-CoV-2 Compounds Using Chemical Structure- and Biological Activity-Based Modeling. J Med Chem 2022; 65:4590-4599. [PMID: 35275639 PMCID: PMC8936051 DOI: 10.1021/acs.jmedchem.1c01372] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2021] [Indexed: 12/12/2022]
Abstract
Identification of anti-SARS-CoV-2 compounds through traditional high-throughput screening (HTS) assays is limited by high costs and low hit rates. To address these challenges, we developed machine learning models to identify compounds acting via inhibition of the entry of SARS-CoV-2 into human host cells or the SARS-CoV-2 3-chymotrypsin-like (3CL) protease. The optimal classification models achieved good performance with area under the receiver operating characteristic curve (AUC-ROC) values of >0.78. Experimental validation showed that the best performing models increased the assay hit rate by 2.1-fold for viral entry inhibitors and 10.4-fold for 3CL protease inhibitors compared to those of the original drug repurposing screens. Twenty-two compounds showed potent (<5 μM) antiviral activities in a SARS-CoV-2 live virus assay. In conclusion, machine learning models can be developed and used as a complementary approach to HTS to expand compound screening capacities and improve the speed and efficiency of anti-SARS-CoV-2 drug discovery.
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Affiliation(s)
- Tuan Xu
- Division of Pre-clinical Innovation, National Center for Advancing Translational Sciences (NCATS), National Institutes of Health (NIH), Rockville, Maryland 20850, United States
| | - Miao Xu
- Division of Pre-clinical Innovation, National Center for Advancing Translational Sciences (NCATS), National Institutes of Health (NIH), Rockville, Maryland 20850, United States
| | - Wei Zhu
- Division of Pre-clinical Innovation, National Center for Advancing Translational Sciences (NCATS), National Institutes of Health (NIH), Rockville, Maryland 20850, United States
| | - Catherine Z Chen
- Division of Pre-clinical Innovation, National Center for Advancing Translational Sciences (NCATS), National Institutes of Health (NIH), Rockville, Maryland 20850, United States
| | - Qi Zhang
- Division of Pre-clinical Innovation, National Center for Advancing Translational Sciences (NCATS), National Institutes of Health (NIH), Rockville, Maryland 20850, United States
| | - Wei Zheng
- Division of Pre-clinical Innovation, National Center for Advancing Translational Sciences (NCATS), National Institutes of Health (NIH), Rockville, Maryland 20850, United States
| | - Ruili Huang
- Division of Pre-clinical Innovation, National Center for Advancing Translational Sciences (NCATS), National Institutes of Health (NIH), Rockville, Maryland 20850, United States
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22
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Xu M, Pradhan M, Gorshkov K, Petersen JD, Shen M, Guo H, Zhu W, Klumpp-Thomas C, Michael S, Itkin M, Itkin Z, Straus MR, Zimmerberg J, Zheng W, Whittaker GR, Chen CZ. A high throughput screening assay for inhibitors of SARS-CoV-2 pseudotyped particle entry. SLAS DISCOVERY : ADVANCING LIFE SCIENCES R & D 2022; 27:86-94. [PMID: 35086793 PMCID: PMC8720380 DOI: 10.1016/j.slasd.2021.12.005] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
Effective small molecule therapies to combat the SARS-CoV-2 infection are still lacking as the COVID-19 pandemic continues globally. High throughput screening assays are needed for lead discovery and optimization of small molecule SARS-CoV-2 inhibitors. In this work, we have applied viral pseudotyping to establish a cell-based SARS-CoV-2 entry assay. Here, the pseudotyped particles (PP) contain SARS-CoV-2 spike in a membrane enveloping both the murine leukemia virus (MLV) gag-pol polyprotein and luciferase reporter RNA. Upon addition of PP to HEK293-ACE2 cells, the SARS-CoV-2 spike protein binds to the ACE2 receptor on the cell surface, resulting in priming by host proteases to trigger endocytosis of these particles, and membrane fusion between the particle envelope and the cell membrane. The internalized luciferase reporter gene is then expressed in cells, resulting in a luminescent readout as a surrogate for spike-mediated entry into cells. This SARS-CoV-2 PP entry assay can be executed in a biosafety level 2 containment lab for high throughput screening. From a collection of 5,158 approved drugs and drug candidates, our screening efforts identified 7 active compounds that inhibited the SARS-CoV-2-S PP entry. Of these seven, six compounds were active against live replicating SARS-CoV-2 virus in a cytopathic effect assay. Our results demonstrated the utility of this assay in the discovery and development of SARS-CoV-2 entry inhibitors as well as the mechanistic study of anti-SARS-CoV-2 compounds. Additionally, particles pseudotyped with spike proteins from SARS-CoV-2 B.1.1.7 and B.1.351 variants were prepared and used to evaluate the therapeutic effects of viral entry inhibitors.
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Affiliation(s)
- Miao Xu
- National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Rockville, MD, 20850, USA
| | - Manisha Pradhan
- National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Rockville, MD, 20850, USA
| | - Kirill Gorshkov
- National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Rockville, MD, 20850, USA
| | - Jennifer D Petersen
- Section on Integrative Biophysics, Division of Basic and Translational Biophysics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA
| | - Min Shen
- National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Rockville, MD, 20850, USA
| | - Hui Guo
- National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Rockville, MD, 20850, USA
| | - Wei Zhu
- National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Rockville, MD, 20850, USA
| | - Carleen Klumpp-Thomas
- National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Rockville, MD, 20850, USA
| | - Sam Michael
- National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Rockville, MD, 20850, USA
| | - Misha Itkin
- National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Rockville, MD, 20850, USA
| | - Zina Itkin
- National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Rockville, MD, 20850, USA
| | - Marco R Straus
- Department of Microbiology and Immunology, College of Veterinary Medicine, Cornell University, T8016C Veterinary Research Tower, Ithaca, NY 14853, USA
| | - Joshua Zimmerberg
- Section on Integrative Biophysics, Division of Basic and Translational Biophysics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA
| | - Wei Zheng
- National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Rockville, MD, 20850, USA
| | - Gary R Whittaker
- Department of Microbiology and Immunology, College of Veterinary Medicine, Cornell University, T8016C Veterinary Research Tower, Ithaca, NY 14853, USA.
| | - Catherine Z Chen
- National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Rockville, MD, 20850, USA.
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23
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Sadremomtaz A, Al-Dahmani ZM, Ruiz-Moreno AJ, Monti A, Wang C, Azad T, Bell JC, Doti N, Velasco-Velázquez MA, de Jong D, de Jonge J, Smit J, Dömling A, van Goor H, Groves MR. Synthetic Peptides That Antagonize the Angiotensin-Converting Enzyme-2 (ACE-2) Interaction with SARS-CoV-2 Receptor Binding Spike Protein. J Med Chem 2022; 65:2836-2847. [PMID: 34328726 PMCID: PMC8353989 DOI: 10.1021/acs.jmedchem.1c00477] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2021] [Indexed: 12/23/2022]
Abstract
The SARS-CoV-2 viral spike protein S receptor-binding domain (S-RBD) binds ACE2 on host cells to initiate molecular events, resulting in intracellular release of the viral genome. Therefore, antagonists of this interaction could allow a modality for therapeutic intervention. Peptides can inhibit the S-RBD:ACE2 interaction by interacting with the protein-protein interface. In this study, protein contact atlas data and molecular dynamics simulations were used to locate interaction hotspots on the secondary structure elements α1, α2, α3, β3, and β4 of ACE2. We designed a library of discontinuous peptides based upon a combination of the hotspot interactions, which were synthesized and screened in a bioluminescence-based assay. The peptides demonstrated high efficacy in antagonizing the SARS-CoV-2 S-RBD:ACE2 interaction and were validated by microscale thermophoresis which demonstrated strong binding affinity (∼10 nM) of these peptides to S-RBD. We anticipate that such discontinuous peptides may hold the potential for an efficient therapeutic treatment for COVID-19.
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Affiliation(s)
- Afsaneh Sadremomtaz
- XB20
Drug Design, Groningen Research Institute of Pharmacy, University of Groningen, 9700 AD Groningen, The Netherlands
| | - Zayana M. Al-Dahmani
- XB20
Drug Design, Groningen Research Institute of Pharmacy, University of Groningen, 9700 AD Groningen, The Netherlands
- Department
of Medical Microbiology and Infection Prevention, University of Groningen, University Medical Center Groningen, 9700RB Groningen, The Netherlands
| | - Angel J. Ruiz-Moreno
- XB20
Drug Design, Groningen Research Institute of Pharmacy, University of Groningen, 9700 AD Groningen, The Netherlands
- Departamento
de Farmacología, Facultad de Medicina, Universidad Nacional Autónoma de Mexico (UNAM), Ciudad de Mexico 04510, Mexico
- Unidad
Periférica de Investigación en Biomedicina Translacional,
Facultad de Medicina, Universidad Nacional
Autónoma de México (UNAM), Félix Cuevas 540, Ciudad de Mexico 03229, Mexico
- Doctorado
en Ciencias Biomédicas, Universidad
Nacional Autónoma de México (UNAM), Ciudad de Mexico 04510, Mexico
| | - Alessandra Monti
- Institute
of Biostructures and Bioimaging (IBB)-CNR, Via Mezzocannone, 16, 80134 Napoli, Italy
| | - Chao Wang
- XB20
Drug Design, Groningen Research Institute of Pharmacy, University of Groningen, 9700 AD Groningen, The Netherlands
| | - Taha Azad
- Center
for
Innovative Cancer Therapeutics, Ottawa Hospital
Research Institute, Ottawa, K1H 8L6 ON, Canada
- Department
of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, K1H 8M5 ON, Canada
| | - John C. Bell
- Center
for
Innovative Cancer Therapeutics, Ottawa Hospital
Research Institute, Ottawa, K1H 8L6 ON, Canada
- Department
of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, K1H 8M5 ON, Canada
| | - Nunzianna Doti
- Institute
of Biostructures and Bioimaging (IBB)-CNR, Via Mezzocannone, 16, 80134 Napoli, Italy
| | - Marco A. Velasco-Velázquez
- Departamento
de Farmacología, Facultad de Medicina, Universidad Nacional Autónoma de Mexico (UNAM), Ciudad de Mexico 04510, Mexico
- Unidad
Periférica de Investigación en Biomedicina Translacional,
Facultad de Medicina, Universidad Nacional
Autónoma de México (UNAM), Félix Cuevas 540, Ciudad de Mexico 03229, Mexico
- Doctorado
en Ciencias Biomédicas, Universidad
Nacional Autónoma de México (UNAM), Ciudad de Mexico 04510, Mexico
| | - Debora de Jong
- Department
of Medical Microbiology and Infection Prevention, University of Groningen, University Medical Center Groningen, 9700RB Groningen, The Netherlands
| | - Jørgen de Jonge
- Centre
for Infectious Disease Control, National
Institute for Public Health and the Environment (RIVM), 3720BA Bilthoven, The Netherlands
| | - Jolanda Smit
- Department
of Medical Microbiology and Infection Prevention, University of Groningen, University Medical Center Groningen, 9700RB Groningen, The Netherlands
| | - Alexander Dömling
- XB20
Drug Design, Groningen Research Institute of Pharmacy, University of Groningen, 9700 AD Groningen, The Netherlands
| | - Harry van Goor
- Department
of Medical Microbiology and Infection Prevention, University of Groningen, University Medical Center Groningen, 9700RB Groningen, The Netherlands
| | - Matthew R. Groves
- XB20
Drug Design, Groningen Research Institute of Pharmacy, University of Groningen, 9700 AD Groningen, The Netherlands
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24
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Dasovich M, Zhuo J, Goodman JA, Thomas A, McPherson RL, Jayabalan AK, Busa VF, Cheng SJ, Murphy BA, Redinger KR, Alhammad YMO, Fehr AR, Tsukamoto T, Slusher BS, Bosch J, Wei H, Leung AKL. High-Throughput Activity Assay for Screening Inhibitors of the SARS-CoV-2 Mac1 Macrodomain. ACS Chem Biol 2022; 17:17-23. [PMID: 34904435 PMCID: PMC8691451 DOI: 10.1021/acschembio.1c00721] [Citation(s) in RCA: 34] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2021] [Accepted: 11/16/2021] [Indexed: 12/11/2022]
Abstract
Macrodomains are a class of conserved ADP-ribosylhydrolases expressed by viruses of pandemic concern, including coronaviruses and alphaviruses. Viral macrodomains are critical for replication and virus-induced pathogenesis; therefore, these enzymes are a promising target for antiviral therapy. However, no potent or selective viral macrodomain inhibitors currently exist, in part due to the lack of a high-throughput assay for this class of enzymes. Here we developed a high-throughput ADP-ribosylhydrolase assay using the SARS-CoV-2 macrodomain Mac1. We performed a pilot screen that identified dasatinib and dihydralazine as ADP-ribosylhydrolase inhibitors. Importantly, dasatinib inhibits SARS-CoV-2 and MERS-CoV Mac1 but not the closest human homologue, MacroD2. Our study demonstrates the feasibility of identifying selective inhibitors based on ADP-ribosylhydrolase activity, paving the way for the screening of large compound libraries to identify improved macrodomain inhibitors and to explore their potential as antiviral therapies for SARS-CoV-2 and future viral threats.
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Affiliation(s)
- Morgan Dasovich
- Department of Biochemistry and Molecular Biology,
Bloomberg School of Public Health, Johns Hopkins University,
Baltimore, Maryland 21205, United States
- Department of Chemistry, Krieger School of Arts and
Sciences, Johns Hopkins University, Baltimore, Maryland 21218,
United States
| | - Junlin Zhuo
- Department of Biochemistry and Molecular Biology,
Bloomberg School of Public Health, Johns Hopkins University,
Baltimore, Maryland 21205, United States
| | - Jack A. Goodman
- Department of Biochemistry and Molecular Biology,
Bloomberg School of Public Health, Johns Hopkins University,
Baltimore, Maryland 21205, United States
| | - Ajit Thomas
- Johns Hopkins Drug Discovery,
Baltimore, Maryland 21205, United States
- Department of Neurology, School of Medicine,
Johns Hopkins University, Baltimore, Maryland 21205,
United States
| | - Robert Lyle McPherson
- Department of Biochemistry and Molecular Biology,
Bloomberg School of Public Health, Johns Hopkins University,
Baltimore, Maryland 21205, United States
| | - Aravinth Kumar Jayabalan
- Department of Biochemistry and Molecular Biology,
Bloomberg School of Public Health, Johns Hopkins University,
Baltimore, Maryland 21205, United States
| | - Veronica F. Busa
- Department of Biochemistry and Molecular Biology,
Bloomberg School of Public Health, Johns Hopkins University,
Baltimore, Maryland 21205, United States
- McKusick-Nathans Department of Genetics Medicine,
School of Medicine, Johns Hopkins
University, Baltimore, Maryland 21205, United
States
| | - Shang-Jung Cheng
- Department of Biochemistry and Molecular Biology,
Bloomberg School of Public Health, Johns Hopkins University,
Baltimore, Maryland 21205, United States
| | - Brennan A. Murphy
- Johns Hopkins Drug Discovery,
Baltimore, Maryland 21205, United States
| | - Karli R. Redinger
- Center for Global Health and Diseases, Case
Western Reserve University, Cleveland, Ohio 44106, United
States
| | - Yousef M. O. Alhammad
- Department of Molecular Biosciences,
University of Kansas, Lawrence, Kansas 66045, United
States
| | - Anthony R. Fehr
- Department of Molecular Biosciences,
University of Kansas, Lawrence, Kansas 66045, United
States
| | - Takashi Tsukamoto
- Johns Hopkins Drug Discovery,
Baltimore, Maryland 21205, United States
- Department of Neurology, School of Medicine,
Johns Hopkins University, Baltimore, Maryland 21205,
United States
| | - Barbara S. Slusher
- Johns Hopkins Drug Discovery,
Baltimore, Maryland 21205, United States
- Department of Neurology, School of Medicine,
Johns Hopkins University, Baltimore, Maryland 21205,
United States
| | - Jürgen Bosch
- Center for Global Health and Diseases, Case
Western Reserve University, Cleveland, Ohio 44106, United
States
- InterRayBio, LLC,
Cleveland, Ohio 44106, United States
| | - Huijun Wei
- Johns Hopkins Drug Discovery,
Baltimore, Maryland 21205, United States
- Department of Neurology, School of Medicine,
Johns Hopkins University, Baltimore, Maryland 21205,
United States
| | - Anthony K. L. Leung
- Department of Biochemistry and Molecular Biology,
Bloomberg School of Public Health, Johns Hopkins University,
Baltimore, Maryland 21205, United States
- McKusick-Nathans Department of Genetics Medicine,
School of Medicine, Johns Hopkins
University, Baltimore, Maryland 21205, United
States
- Department of Oncology and Department of
Molecular Biology and Genetics, School of Medicine, Johns Hopkins
University, Baltimore, Maryland 21205, United
States
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25
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DrugDevCovid19: An Atlas of Anti-COVID-19 Compounds Derived by Computer-Aided Drug Design. Molecules 2022; 27:molecules27030683. [PMID: 35163948 PMCID: PMC8838031 DOI: 10.3390/molecules27030683] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2021] [Revised: 01/06/2022] [Accepted: 01/11/2022] [Indexed: 01/18/2023] Open
Abstract
Since the outbreak of SARS-CoV-2, numerous compounds against COVID-19 have been derived by computer-aided drug design (CADD) studies. They are valuable resources for the development of COVID-19 therapeutics. In this work, we reviewed these studies and analyzed 779 compounds against 16 target proteins from 181 CADD publications. We performed unified docking simulations and neck-to-neck comparison with the solved co-crystal structures. We computed their chemical features and classified these compounds, aiming to provide insights for subsequent drug design. Through detailed analyses, we recommended a batch of compounds that are worth further study. Moreover, we organized all the abundant data and constructed a freely available database, DrugDevCovid19, to facilitate the development of COVID-19 therapeutics.
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26
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Gorshkov K, Morales Vasquez D, Chiem K, Ye C, Nguyen Tran B, Carlos de la Torre J, Moran T, Chen CZ, Martinez-Sobrido L, Zheng W. SARS-CoV-2 Nucleocapsid Protein TR-FRET Assay Amenable to High Throughput Screening. ACS Pharmacol Transl Sci 2022; 5:8-19. [PMID: 35036857 PMCID: PMC8751018 DOI: 10.1021/acsptsci.1c00182] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2021] [Indexed: 12/24/2022]
Abstract
![]()
Drug
development for specific antiviral agents against coronavirus
disease 2019 (COVID-19) is still an unmet medical need as the pandemic
continues to spread globally. Although huge efforts for drug repurposing
and compound screens have been put forth, only a few compounds are
in late-stage clinical trials. New approaches and assays are needed
to accelerate COVID-19 drug discovery and development. Here, we report
a time-resolved fluorescence resonance energy transfer-based assay
that detects the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)
nucleocapsid protein (NP) produced in infected cells. It uses two
specific anti-NP monoclonal antibodies conjugated to donor and acceptor
fluorophores that produce a robust ratiometric signal for high throughput
screening of large compound collections. Using this assay, we measured
a half maximal inhibitory concentration (IC50) for remdesivir
of 9.3 μM against infection with SARS-CoV-2 USA/WA1/2020 (WA-1).
The assay also detected SARS-CoV-2 South African (Beta, β),
Brazilian/Japanese P.1 (Gamma, γ), and Californian (Epsilon,
ε) variants of concern (VoC). Therefore, this homogeneous SARS-CoV-2
NP detection assay can be used for accelerating lead compound discovery
for drug development and for evaluating drug efficacy against emerging
SARS-CoV-2 VoC.
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Affiliation(s)
- Kirill Gorshkov
- National Center for Advancing Translational Sciences, 9800 Medical Center Drive, Rockville, Maryland 20850, United States
| | - Desarey Morales Vasquez
- Texas Biomedical Research Institute, 8715 West Military Drive, San Antonio, Texas 78227, United States
| | - Kevin Chiem
- Texas Biomedical Research Institute, 8715 West Military Drive, San Antonio, Texas 78227, United States
| | - Chengjin Ye
- Texas Biomedical Research Institute, 8715 West Military Drive, San Antonio, Texas 78227, United States
| | - Bruce Nguyen Tran
- National Center for Advancing Translational Sciences, 9800 Medical Center Drive, Rockville, Maryland 20850, United States
| | - Juan Carlos de la Torre
- Department of Immunology and Microbiology, IMM6, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, United States
| | - Thomas Moran
- Icahn School of Medicine, Mt. Sinai, 1 Gustave L. Levy Place, New York, New York 10029, United States
| | - Catherine Z Chen
- National Center for Advancing Translational Sciences, 9800 Medical Center Drive, Rockville, Maryland 20850, United States
| | - Luis Martinez-Sobrido
- Texas Biomedical Research Institute, 8715 West Military Drive, San Antonio, Texas 78227, United States
| | - Wei Zheng
- National Center for Advancing Translational Sciences, 9800 Medical Center Drive, Rockville, Maryland 20850, United States
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27
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Leung AKL, Griffin DE, Bosch J, Fehr AR. The Conserved Macrodomain Is a Potential Therapeutic Target for Coronaviruses and Alphaviruses. Pathogens 2022; 11:pathogens11010094. [PMID: 35056042 PMCID: PMC8780475 DOI: 10.3390/pathogens11010094] [Citation(s) in RCA: 28] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2021] [Revised: 01/07/2022] [Accepted: 01/11/2022] [Indexed: 12/04/2022] Open
Abstract
Emerging and re-emerging viral diseases pose continuous public health threats, and effective control requires a combination of non-pharmacologic interventions, treatment with antivirals, and prevention with vaccines. The COVID-19 pandemic has demonstrated that the world was least prepared to provide effective treatments. This lack of preparedness has been due, in large part, to a lack of investment in developing a diverse portfolio of antiviral agents, particularly those ready to combat viruses of pandemic potential. Here, we focus on a drug target called macrodomain that is critical for the replication and pathogenesis of alphaviruses and coronaviruses. Some mutations in alphavirus and coronaviral macrodomains are not tolerated for virus replication. In addition, the coronavirus macrodomain suppresses host interferon responses. Therefore, macrodomain inhibitors have the potential to block virus replication and restore the host’s protective interferon response. Viral macrodomains offer an attractive antiviral target for developing direct acting antivirals because they are highly conserved and have a structurally well-defined (druggable) binding pocket. Given that this target is distinct from the existing RNA polymerase and protease targets, a macrodomain inhibitor may complement current approaches, pre-empt the threat of resistance and offer opportunities to develop combination therapies for combating COVID-19 and future viral threats.
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Affiliation(s)
- Anthony K. L. Leung
- Department of Biochemistry and Molecular Biology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD 21205, USA
- Department of Oncology, School of Medicine, Johns Hopkins University, Baltimore, MD 21205, USA
- McKusick-Nathans Department of Genetic Medicine, School of Medicine, Johns Hopkins University, Baltimore, MD 21205, USA
- Department of Molecular Biology and Genetics, School of Medicine, Johns Hopkins University, Baltimore, MD 21205, USA
- Correspondence: (A.K.L.L.); (D.E.G.); (A.R.F.); Tel.: +1-(410)-5028939 (A.K.L.L.); +1-(410)-955-3459 (D.E.G.); +1-(785)-864-6626 (A.R.F.)
| | - Diane E. Griffin
- W. Harry Feinstone Department of Molecular Microbiology and Immunology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD 21205, USA
- Correspondence: (A.K.L.L.); (D.E.G.); (A.R.F.); Tel.: +1-(410)-5028939 (A.K.L.L.); +1-(410)-955-3459 (D.E.G.); +1-(785)-864-6626 (A.R.F.)
| | - Jürgen Bosch
- Center for Global Health and Diseases, Case Western Reserve University, Cleveland, OH 44106, USA;
- InterRayBio, LLC, Cleveland, OH 44106, USA
| | - Anthony R. Fehr
- Department of Molecular Biosciences, University of Kansas, Lawrence, KS 66045, USA
- Correspondence: (A.K.L.L.); (D.E.G.); (A.R.F.); Tel.: +1-(410)-5028939 (A.K.L.L.); +1-(410)-955-3459 (D.E.G.); +1-(785)-864-6626 (A.R.F.)
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28
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Clyde A, Galanie S, Kneller DW, Ma H, Babuji Y, Blaiszik B, Brace A, Brettin T, Chard K, Chard R, Coates L, Foster I, Hauner D, Kertesz V, Kumar N, Lee H, Li Z, Merzky A, Schmidt JG, Tan L, Titov M, Trifan A, Turilli M, Van Dam H, Chennubhotla SC, Jha S, Kovalevsky A, Ramanathan A, Head MS, Stevens R. High-Throughput Virtual Screening and Validation of a SARS-CoV-2 Main Protease Noncovalent Inhibitor. J Chem Inf Model 2022; 62:116-128. [PMID: 34793155 PMCID: PMC8610012 DOI: 10.1021/acs.jcim.1c00851] [Citation(s) in RCA: 64] [Impact Index Per Article: 21.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2021] [Indexed: 12/27/2022]
Abstract
Despite the recent availability of vaccines against the acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the search for inhibitory therapeutic agents has assumed importance especially in the context of emerging new viral variants. In this paper, we describe the discovery of a novel noncovalent small-molecule inhibitor, MCULE-5948770040, that binds to and inhibits the SARS-Cov-2 main protease (Mpro) by employing a scalable high-throughput virtual screening (HTVS) framework and a targeted compound library of over 6.5 million molecules that could be readily ordered and purchased. Our HTVS framework leverages the U.S. supercomputing infrastructure achieving nearly 91% resource utilization and nearly 126 million docking calculations per hour. Downstream biochemical assays validate this Mpro inhibitor with an inhibition constant (Ki) of 2.9 μM (95% CI 2.2, 4.0). Furthermore, using room-temperature X-ray crystallography, we show that MCULE-5948770040 binds to a cleft in the primary binding site of Mpro forming stable hydrogen bond and hydrophobic interactions. We then used multiple μs-time scale molecular dynamics (MD) simulations and machine learning (ML) techniques to elucidate how the bound ligand alters the conformational states accessed by Mpro, involving motions both proximal and distal to the binding site. Together, our results demonstrate how MCULE-5948770040 inhibits Mpro and offers a springboard for further therapeutic design.
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Affiliation(s)
- Austin Clyde
- Data Science and Learning Division,
Argonne National Laboratory, Lemont, Illinois 60439,
United States
- Department of Computer Science,
University of Chicago, Chicago, Illinois 60615,
United States
- National Virtual Biotechnology
Laboratory, Washington, District of Columbia 20585, United
States
| | - Stephanie Galanie
- Biosciences Division, Oak Ridge National
Laboratory, Oak Ridge, Tennessee 37831, United
States
- National Virtual Biotechnology
Laboratory, Washington, District of Columbia 20585, United
States
| | - Daniel W. Kneller
- Neutron Scattering Division, Oak Ridge
National Laboratory, Oak Ridge, Tennessee 37831, United
States
- National Virtual Biotechnology
Laboratory, Washington, District of Columbia 20585, United
States
| | - Heng Ma
- Data Science and Learning Division,
Argonne National Laboratory, Lemont, Illinois 60439,
United States
- National Virtual Biotechnology
Laboratory, Washington, District of Columbia 20585, United
States
| | - Yadu Babuji
- Department of Computer Science,
University of Chicago, Chicago, Illinois 60615,
United States
- National Virtual Biotechnology
Laboratory, Washington, District of Columbia 20585, United
States
| | - Ben Blaiszik
- Data Science and Learning Division,
Argonne National Laboratory, Lemont, Illinois 60439,
United States
- National Virtual Biotechnology
Laboratory, Washington, District of Columbia 20585, United
States
| | - Alexander Brace
- Data Science and Learning Division,
Argonne National Laboratory, Lemont, Illinois 60439,
United States
- Department of Computer Science,
University of Chicago, Chicago, Illinois 60615,
United States
- National Virtual Biotechnology
Laboratory, Washington, District of Columbia 20585, United
States
| | - Thomas Brettin
- Computing Environment and Life Sciences Directorate,
Argonne National Laboratory, Lemont, Illinois 60439,
United States
- National Virtual Biotechnology
Laboratory, Washington, District of Columbia 20585, United
States
| | - Kyle Chard
- Department of Computer Science,
University of Chicago, Chicago, Illinois 60615,
United States
- National Virtual Biotechnology
Laboratory, Washington, District of Columbia 20585, United
States
| | - Ryan Chard
- Data Science and Learning Division,
Argonne National Laboratory, Lemont, Illinois 60439,
United States
- Department of Computer Science,
University of Chicago, Chicago, Illinois 60615,
United States
- National Virtual Biotechnology
Laboratory, Washington, District of Columbia 20585, United
States
| | - Leighton Coates
- Neutron Scattering Division, Oak Ridge
National Laboratory, Oak Ridge, Tennessee 37831, United
States
- National Virtual Biotechnology
Laboratory, Washington, District of Columbia 20585, United
States
| | - Ian Foster
- Data Science and Learning Division,
Argonne National Laboratory, Lemont, Illinois 60439,
United States
- Department of Computer Science,
University of Chicago, Chicago, Illinois 60615,
United States
- National Virtual Biotechnology
Laboratory, Washington, District of Columbia 20585, United
States
| | - Darin Hauner
- Computational Biology Group, Biological Science Division,
Pacific Northwest National Laboratory, Richland, Washington
99352, United States
- National Virtual Biotechnology
Laboratory, Washington, District of Columbia 20585, United
States
| | - Vlimos Kertesz
- Neutron Scattering Division, Oak Ridge
National Laboratory, Oak Ridge, Tennessee 37831, United
States
- National Virtual Biotechnology
Laboratory, Washington, District of Columbia 20585, United
States
| | - Neeraj Kumar
- Computational Biology Group, Biological Science Division,
Pacific Northwest National Laboratory, Richland, Washington
99352, United States
- National Virtual Biotechnology
Laboratory, Washington, District of Columbia 20585, United
States
| | - Hyungro Lee
- Department of Electrical and Computer Engineering,
Rutgers University, Piscataway, New Jersey 08854,
United States
- National Virtual Biotechnology
Laboratory, Washington, District of Columbia 20585, United
States
| | - Zhuozhao Li
- Data Science and Learning Division,
Argonne National Laboratory, Lemont, Illinois 60439,
United States
- Department of Computer Science,
University of Chicago, Chicago, Illinois 60615,
United States
- National Virtual Biotechnology
Laboratory, Washington, District of Columbia 20585, United
States
| | - Andre Merzky
- Department of Electrical and Computer Engineering,
Rutgers University, Piscataway, New Jersey 08854,
United States
- National Virtual Biotechnology
Laboratory, Washington, District of Columbia 20585, United
States
| | - Jurgen G. Schmidt
- Bioscience Division, Los Alamos National
Laboratory, Los Alamos, New Mexico 87545, United
States
- National Virtual Biotechnology
Laboratory, Washington, District of Columbia 20585, United
States
| | - Li Tan
- Department of Electrical and Computer Engineering,
Rutgers University, Piscataway, New Jersey 08854,
United States
- National Virtual Biotechnology
Laboratory, Washington, District of Columbia 20585, United
States
| | - Mikhail Titov
- Department of Electrical and Computer Engineering,
Rutgers University, Piscataway, New Jersey 08854,
United States
- National Virtual Biotechnology
Laboratory, Washington, District of Columbia 20585, United
States
| | - Anda Trifan
- University of Illinois at
Urbana-Champaign, Champaign, Illinois 61820, United
States
- National Virtual Biotechnology
Laboratory, Washington, District of Columbia 20585, United
States
| | - Matteo Turilli
- Department of Electrical and Computer Engineering,
Rutgers University, Piscataway, New Jersey 08854,
United States
- Computational Science Initiative,
Brookhaven National Laboratory, Upton, New York 11973,
United States
- National Virtual Biotechnology
Laboratory, Washington, District of Columbia 20585, United
States
| | - Hubertus Van Dam
- Computational Science Initiative,
Brookhaven National Laboratory, Upton, New York 11973,
United States
- National Virtual Biotechnology
Laboratory, Washington, District of Columbia 20585, United
States
| | - Srinivas C. Chennubhotla
- Department of Computational and Systems
Biology, University of Pittsburgh, Pittsburgh, Pennsylvania
15260, United States
- National Virtual Biotechnology
Laboratory, Washington, District of Columbia 20585, United
States
| | - Shantenu Jha
- Department of Electrical and Computer Engineering,
Rutgers University, Piscataway, New Jersey 08854,
United States
- Computational Science Initiative,
Brookhaven National Laboratory, Upton, New York 11973,
United States
- National Virtual Biotechnology
Laboratory, Washington, District of Columbia 20585, United
States
| | - Andrey Kovalevsky
- Second Target Station, Oak Ridge
National Laboratory, Oak Ridge, Tennessee 37831, United
States
- National Virtual Biotechnology
Laboratory, Washington, District of Columbia 20585, United
States
| | - Arvind Ramanathan
- Data Science and Learning Division,
Argonne National Laboratory, Lemont, Illinois 60439,
United States
- National Virtual Biotechnology
Laboratory, Washington, District of Columbia 20585, United
States
| | - Martha S. Head
- Joint Institute for Biological Sciences,
Oak Ridge National Laboratory, Oak Ridge, Tennessee 37831,
United States
- National Virtual Biotechnology
Laboratory, Washington, District of Columbia 20585, United
States
| | - Rick Stevens
- Department of Computer Science,
University of Chicago, Chicago, Illinois 60615,
United States
- Computing Environment and Life Sciences Directorate,
Argonne National Laboratory, Lemont, Illinois 60439,
United States
- National Virtual Biotechnology
Laboratory, Washington, District of Columbia 20585, United
States
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Bouchiba Y, Ruffini M, Schiex T, Barbe S. Computational Design of Miniprotein Binders. Methods Mol Biol 2022; 2405:361-382. [PMID: 35298822 DOI: 10.1007/978-1-0716-1855-4_17] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/14/2023]
Abstract
Miniprotein binders hold a great interest as a class of drugs that bridges the gap between monoclonal antibodies and small molecule drugs. Like monoclonal antibodies, they can be designed to bind to therapeutic targets with high affinity, but they are more stable and easier to produce and to administer. In this chapter, we present a structure-based computational generic approach for miniprotein inhibitor design. Specifically, we describe step-by-step the implementation of the approach for the design of miniprotein binders against the SARS-CoV-2 coronavirus, using available structural data on the SARS-CoV-2 spike receptor binding domain (RBD) in interaction with its native target, the human receptor ACE2. Structural data being increasingly accessible around many protein-protein interaction systems, this method might be applied to the design of miniprotein binders against numerous therapeutic targets. The computational pipeline exploits provable and deterministic artificial intelligence-based protein design methods, with some recent additions in terms of binding energy estimation, multistate design and diverse library generation.
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Affiliation(s)
- Younes Bouchiba
- TBI, Université de Toulouse, CNRS, INRAE, INSA, ANITI, Toulouse, France
| | - Manon Ruffini
- TBI, Université de Toulouse, CNRS, INRAE, INSA, ANITI, Toulouse, France
- Université Fédérale de Toulouse, ANITI, INRAE, UR 875, Toulouse, France
| | - Thomas Schiex
- Université Fédérale de Toulouse, ANITI, INRAE, UR 875, Toulouse, France
| | - Sophie Barbe
- TBI, Université de Toulouse, CNRS, INRAE, INSA, ANITI, Toulouse, France.
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30
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Xu YM, Inacio MC, Liu MX, Gunatilaka AAL. Discovery of diminazene as a dual inhibitor of SARS-CoV-2 human host proteases TMPRSS2 and furin using cell-based assays. CURRENT RESEARCH IN CHEMICAL BIOLOGY 2022; 2:100023. [PMID: 35815069 PMCID: PMC8920474 DOI: 10.1016/j.crchbi.2022.100023] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
The proteases TMPRSS2 (transmembrane protease serine 2) and furin are known to play important roles in viral infectivity including systematic COVID-19 infection through priming of the spike protein of SARS-CoV-2 and related viruses. To discover small-molecules capable of inhibiting these host proteases, we established convenient and cost-effective cell-based assays employing Vero cells overexpressing TMPRSS2 and furin. A cell-based proteolytic assay for broad-spectrum protease inhibitors was also established using human prostate cancer cell line LNCaP. Evaluation of camostat, nafamostat, and gabexate in these cell-based assays confirmed their known TMPRSS2 inhibitory activities. Diminazene, a veterinary medicinal agent and a known furin inhibitor was found to inhibit both TMPRSS2 and furin with IC50s of 1.35 and 13.2 μM, respectively. Establishment and the use of cell-based assays for evaluation TMPRSS2 and furin inhibitory activity and implications of dual activity of diminazene vs TMPRSS2 and furin are presented.
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Affiliation(s)
- Ya-Ming Xu
- Southwest Center for Natural Products Research, School of Natural Resources and the Environment, College of Agriculture and Life Sciences, University of Arizona, Tucson, AZ 85706, USA
| | - Marielle Cascaes Inacio
- Southwest Center for Natural Products Research, School of Natural Resources and the Environment, College of Agriculture and Life Sciences, University of Arizona, Tucson, AZ 85706, USA
| | - Manping X Liu
- Southwest Center for Natural Products Research, School of Natural Resources and the Environment, College of Agriculture and Life Sciences, University of Arizona, Tucson, AZ 85706, USA
| | - A A Leslie Gunatilaka
- Southwest Center for Natural Products Research, School of Natural Resources and the Environment, College of Agriculture and Life Sciences, University of Arizona, Tucson, AZ 85706, USA
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31
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Dutta D, Liu J, Xiong H. NLRP3 inflammasome activation and SARS-CoV-2-mediated hyperinflammation, cytokine storm and neurological syndromes. INTERNATIONAL JOURNAL OF PHYSIOLOGY, PATHOPHYSIOLOGY AND PHARMACOLOGY 2022; 14:138-160. [PMID: 35891930 PMCID: PMC9301183] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Subscribe] [Scholar Register] [Received: 04/01/2022] [Accepted: 05/02/2022] [Indexed: 04/13/2023]
Abstract
Despite the introduction of vaccines and drugs for SARS-CoV-2, the COVID-19 pandemic continues to spread throughout the world. In severe COVID-19 patients, elevated levels of proinflammatory cytokines have been detected in the blood, lung cells, and bronchoalveolar lavage, which is referred to as a cytokine storm, a consequence of overactivation of the NLR family pyrin domain-containing protein 3 (NLRP3) inflammasome and resultant excessive cytokine production. The hyperinflammatory response and cytokine storm cause multiorgan impairment including the central nervous system, in addition to a detriment to the respiratory system. Hyperactive NLRP3 inflammasome, due to dysregulated immune response, is the primary cause of COVID-19 severity. The severity could be enhanced due to viral evolution leading to the emergence of mutated variants of concern, such as delta and omicron. In this review, we elaborate on the inflammatory responses associated with the NLRP3 inflammasome activation in COVID-19 pathogenesis, the mechanisms for the NLRP3 inflammasome activation and pathway involved, cytokine storm, and neurological complications as long-term consequences of SARS-CoV-2 infection. Also discussed is the therapeutic potential of NLRP3 inflammasome inhibitors for the treatment of COVID-19.
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Affiliation(s)
- Debashis Dutta
- Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center Omaha, NE 68198-5880, USA
| | - Jianuo Liu
- Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center Omaha, NE 68198-5880, USA
| | - Huangui Xiong
- Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center Omaha, NE 68198-5880, USA
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32
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Law MF, Ho R, Law KWT, Cheung CKM. Gastrointestinal and hepatic side effects of potential treatment for COVID-19 and vaccination in patients with chronic liver diseases. World J Hepatol 2021; 13:1850-1874. [PMID: 35069994 PMCID: PMC8727202 DOI: 10.4254/wjh.v13.i12.1850] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/06/2021] [Revised: 07/20/2021] [Accepted: 11/15/2021] [Indexed: 02/06/2023] Open
Abstract
The outbreak of coronavirus disease 2019 (COVID-19) is a global pandemic. Many clinical trials have been performed to investigate potential treatments or vaccines for this disease to reduce the high morbidity and mortality. The drugs of higher interest include umifenovir, bromhexine, remdesivir, lopinavir/ritonavir, steroid, tocilizumab, interferon alpha or beta, ribavirin, fivapiravir, nitazoxanide, ivermectin, molnupiravir, hydroxychloroquine/chloroquine alone or in combination with azithromycin, and baricitinib. Gastrointestinal (GI) symptoms and liver dysfunction are frequently seen in patients with COVID-19, which can make it difficult to differentiate disease manifestations from treatment adverse effects. GI symptoms of COVID-19 include anorexia, dyspepsia, nausea, vomiting, diarrhea and abdominal pain. Liver injury can be a result of systemic inflammation or cytokine storm, or due to the adverse drug effects in patients who have been receiving different treatments. Regular monitoring of liver function should be performed. COVID-19 vaccines have been rapidly developed with different technologies including mRNA, viral vectors, inactivated viruses, recombinant DNA, protein subunits and live attenuated viruses. Patients with chronic liver disease or inflammatory bowel disease and liver transplant recipients are encouraged to receive vaccination as the benefits outweigh the risks. Vaccination against COVID-19 is also recommended to family members and healthcare professionals caring for these patients to reduce exposure to the severe acute respiratory syndrome coronavirus 2 virus.
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Affiliation(s)
- Man Fai Law
- Department of Medicine and Therapeutics, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, China.
| | - Rita Ho
- Department of Medicine, North District Hospital, Hong Kong, China
| | | | - Carmen Ka Man Cheung
- Department of Medicine and Therapeutics, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, China
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33
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Ma LL, Liu HM, Liu XM, Yuan XY, Xu C, Wang F, Lin JZ, Xu RC, Zhang DK. Screening S protein - ACE2 blockers from natural products: Strategies and advances in the discovery of potential inhibitors of COVID-19. Eur J Med Chem 2021; 226:113857. [PMID: 34628234 PMCID: PMC8489279 DOI: 10.1016/j.ejmech.2021.113857] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2021] [Revised: 09/11/2021] [Accepted: 09/15/2021] [Indexed: 02/09/2023]
Abstract
The Coronavirus disease, 2019 (COVID-19) is caused by severe acute respiratory syndrome Coronavirus 2 (SARS-CoV-2), which poses a major threat to human life and health. Given its continued development, limiting the spread of COVID-19 in the population remains a challenging task. Currently, multiple therapies are being tried around the world to deal with SARS-CoV-2 infection, and a variety of studies have shown that natural products have a significant effect on COVID-19 patients. The combination of SARS-CoV-2 S protein with Angiotensin converting enzyme II(ACE2) of host cell to promote membrane fusion is an initial critical step for SARS-CoV-2 infection. Therefore, screening natural products that inhibit the binding of SARS-CoV-2 S protein and ACE2 also provides a feasible strategy for the treatment of COVID-19. Establishment of high throughput screening model is an important basis and key technology for screening S protein-ACE2 blockers. Based on this, the molecular structures of SARS-CoV-2 and ACE2 and their processes in the life cycle of SARS-CoV-2 and host cell infection were firstly reviewed in this paper, with emphasis on the methods and techniques of screening S protein-ACE2 blockers, including Virtual Screening (VS), Surface Plasmon Resonance (SPR), Biochromatography, Biotin-avidin with Enzyme-linked Immunosorbent assay and Gene Chip Technology. Furthermore, the technical principle, advantages and disadvantages and application scope were further elaborated. Combined with the application of the above screening technologies in S protein-ACE2 blockers, a variety of natural products, such as flavonoids, terpenoids, phenols, alkaloids, were summarized, which could be used as S protein-ACE2 blockers, in order to provide ideas for the efficient discovery of S protein-ACE2 blockers from natural sources and contribute to the development of broad-spectrum anti coronavirus drugs.
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Affiliation(s)
- Le-le Ma
- State Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, PR China
| | - Hui-Min Liu
- State Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, PR China
| | - Xue-Mei Liu
- State Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, PR China
| | - Xiao-Yu Yuan
- State Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, PR China
| | - Chao Xu
- State Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, PR China
| | - Fang Wang
- Key Laboratory of Modern Chinese Medicine Preparation of Ministry of Education, Jiangxi University of Traditional Chinese Medicine Central Laboratory, Nanchang, 330000, PR China
| | - Jun-Zhi Lin
- TCM Regulating Metabolic Diseases Key Laboratory of Sichuan Province, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, 610072, PR China.
| | - Run-Chun Xu
- State Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, PR China.
| | - Ding-Kun Zhang
- State Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, PR China.
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Lochab A, Thareja R, Gadre SD, Saxena R. Potential Protein and Enzyme Targets for In‐silico Development and Repurposing of Drug Against Coronaviruses. ChemistrySelect 2021. [DOI: 10.1002/slct.202103350] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Affiliation(s)
- Amit Lochab
- Department of Chemistry Kirori Mal College University of Delhi Delhi India
| | - Rakhi Thareja
- Department of Chemistry St. Stephens College University of Delhi Delhi India
| | - Sangeeta D. Gadre
- Department of Physics Kirori Mal College University of Delhi Delhi India
| | - Reena Saxena
- Department of Chemistry Kirori Mal College University of Delhi Delhi India
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Zhao J, Zhang G, Zhang Y, Yi D, Li Q, Ma L, Guo S, Li X, Guo F, Lin R, Luu G, Liu Z, Wang Y, Cen S. 2-((1H-indol-3-yl)thio)-N-phenyl-acetamides: SARS-CoV-2 RNA-dependent RNA polymerase inhibitors. Antiviral Res 2021; 196:105209. [PMID: 34801588 PMCID: PMC8600920 DOI: 10.1016/j.antiviral.2021.105209] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2021] [Revised: 11/03/2021] [Accepted: 11/15/2021] [Indexed: 01/19/2023]
Abstract
Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is the causative agent of Coronavirus Disease 2019 (COVID-19) pandemic. Despite intensive and global efforts to discover and develop novel antiviral therapies, only Remdesivir has been approved as a treatment for COVID-19. Therefore, effective antiviral therapeutics are still urgently needed to combat and halt the pandemic. Viral RNA-dependent RNA polymerase (RdRp) of SARS-CoV-2 demonstrates high potential as a reliable target for the development of antivirals. We previously developed a cell-based assay to assess the efficiency of compounds that target SARS-CoV-2 RdRp, as well as their tolerance to viral exoribonuclease-mediated proof-reading. In our previous study, we discovered that 2-((1H-indol-3-yl)thio)-N-phenyl-acetamides specifically targets the RdRp of both respiratory syncytial virus (RSV) and influenza A virus. Thus, we hypothesize that 2-((1H-indol-3-yl)thio)-N-phenyl-acetamides may also have the ability to inhibit SARS-CoV-2 replication by targeting its RdRp activity. In this research, we test a compound library containing 103 of 2-((1H-indol-3-yl)thio)-N-phenyl-acetamides against SARS-CoV-2 RdRp, using our cell-based assay. Among these compounds, the top five candidates strongly inhibit SARS-CoV-2 RdRp activity while exhibiting low cytotoxicity and resistance to viral exoribonuclease. Compound 6-72-2a is the most promising candidate with the lowest EC50 value of 1.41 μM and highest selectivity index (CC50/EC50) (above 70.92). Furthermore, our data suggests that 4–46b and 6-72-2a also inhibit the replication of HCoV-OC43 and HCoV-NL63 virus in a dose-dependent manner. Compounds 4–46b and 6-72-2a exhibit EC50 values of 1.13 μM and 0.94 μM, respectively, on HCoV-OC43 viral replication. However, higher concentrations of these compounds are needed to effectively block HCoV-NL63 replication. Together, our findings successfully identified 4–46b and 6-72-2a as promising inhibitors against SARS-CoV-2 RdRp.
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Affiliation(s)
- Jianyuan Zhao
- Institute of Medicinal Biotechnology, Chinese Academy of Medical Science, Beijing, China
| | - Guoning Zhang
- Institute of Medicinal Biotechnology, Chinese Academy of Medical Science, Beijing, China
| | - Yongxin Zhang
- Institute of Medicinal Biotechnology, Chinese Academy of Medical Science, Beijing, China
| | - Dongrong Yi
- Institute of Medicinal Biotechnology, Chinese Academy of Medical Science, Beijing, China
| | - Quanjie Li
- Institute of Medicinal Biotechnology, Chinese Academy of Medical Science, Beijing, China
| | - Ling Ma
- Institute of Medicinal Biotechnology, Chinese Academy of Medical Science, Beijing, China
| | - SaiSai Guo
- Institute of Medicinal Biotechnology, Chinese Academy of Medical Science, Beijing, China
| | - Xiaoyu Li
- Institute of Medicinal Biotechnology, Chinese Academy of Medical Science, Beijing, China
| | - Fei Guo
- Institute of Pathogen Biology, Chinese Academy of Medical Science, Beijing, China
| | - Rongtuan Lin
- Lady Davis Institute for Medical Research, McGill University and Jewish General Hospital, Montreal, Quebec, Canada
| | - Gia Luu
- Lady Davis Institute for Medical Research, McGill University and Jewish General Hospital, Montreal, Quebec, Canada
| | - Zhenlong Liu
- Lady Davis Institute for Medical Research, McGill University and Jewish General Hospital, Montreal, Quebec, Canada.
| | - Yucheng Wang
- Institute of Medicinal Biotechnology, Chinese Academy of Medical Science, Beijing, China.
| | - Shan Cen
- Institute of Medicinal Biotechnology, Chinese Academy of Medical Science, Beijing, China.
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36
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Shagufta, Ahmad I. An Update on Pharmacological Relevance and Chemical Synthesis of Natural Products and Derivatives with Anti SARS-CoV-2 Activity. ChemistrySelect 2021; 6:11502-11527. [PMID: 34909460 PMCID: PMC8661826 DOI: 10.1002/slct.202103301] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2021] [Accepted: 10/25/2021] [Indexed: 01/18/2023]
Abstract
Natural products recognized traditionally as a vital source of active constituents in pharmacotherapy. The COVID-19 infection caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is highly transmissible, pathogenic, and considered an ongoing global health emergency. The emergence of COVID-19 globally and the lack of adequate treatment brought attention towards herbal medicines, and scientists across the globe instigated the search for novel drugs from medicinal plants and natural products to tackle this deadly virus. The natural products rich in scaffold diversity and structural complexity are an excellent source for antiviral drug discovery. Recently the investigation of several natural products and their synthetic derivatives resulted in the identification of promising anti SARS-CoV-2 agents. This review article will highlight the pharmacological relevance and chemical synthesis of the recently discovered natural product and their synthetic analogs as SARS-CoV-2 inhibitors. The summarized information will pave the path for the natural product-based drug discovery of safe and potent antiviral agents, particularly against SARS-CoV-2.
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Affiliation(s)
- Shagufta
- Department of Mathematics and Natural SciencesSchool of Arts and SciencesAmerican University of Ras Al KhaimahRas Al Khaimah Road, P. O. Box10021Ras Al Khaimah, UAE
| | - Irshad Ahmad
- Department of Mathematics and Natural SciencesSchool of Arts and SciencesAmerican University of Ras Al KhaimahRas Al Khaimah Road, P. O. Box10021Ras Al Khaimah, UAE
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37
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Cumpstey AF, Clark AD, Santolini J, Jackson AA, Feelisch M. COVID-19: A Redox Disease-What a Stress Pandemic Can Teach Us About Resilience and What We May Learn from the Reactive Species Interactome About Its Treatment. Antioxid Redox Signal 2021; 35:1226-1268. [PMID: 33985343 DOI: 10.1089/ars.2021.0017] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Significance: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus causing coronavirus disease 2019 (COVID-19), affects every aspect of human life by challenging bodily, socioeconomic, and political systems at unprecedented levels. As vaccines become available, their distribution, safety, and efficacy against emerging variants remain uncertain, and specific treatments are lacking. Recent Advances: Initially affecting the lungs, COVID-19 is a complex multisystems disease that disturbs the whole-body redox balance and can be long-lasting (Long-COVID). Numerous risk factors have been identified, but the reasons for variations in susceptibility to infection, disease severity, and outcome are poorly understood. The reactive species interactome (RSI) was recently introduced as a framework to conceptualize how cells and whole organisms sense, integrate, and accommodate stress. Critical Issues: We here consider COVID-19 as a redox disease, offering a holistic perspective of its effects on the human body, considering the vulnerability of complex interconnected systems with multiorgan/multilevel interdependencies. Host/viral glycan interactions underpin SARS-CoV-2's extraordinary efficiency in gaining cellular access, crossing the epithelial/endothelial barrier to spread along the vascular/lymphatic endothelium, and evading antiviral/antioxidant defences. An inflammation-driven "oxidative storm" alters the redox landscape, eliciting epithelial, endothelial, mitochondrial, metabolic, and immune dysfunction, and coagulopathy. Concomitantly reduced nitric oxide availability renders the sulfur-based redox circuitry vulnerable to oxidation, with eventual catastrophic failure in redox communication/regulation. Host nutrient limitations are crucial determinants of resilience at the individual and population level. Future Directions: While inflicting considerable damage to health and well-being, COVID-19 may provide the ultimate testing ground to improve the diagnosis and treatment of redox-related stress diseases. "Redox phenotyping" of patients to characterize whole-body RSI status as the disease progresses may inform new therapeutic approaches to regain redox balance, reduce mortality in COVID-19 and other redox diseases, and provide opportunities to tackle Long-COVID. Antioxid. Redox Signal. 35, 1226-1268.
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Affiliation(s)
- Andrew F Cumpstey
- Respiratory and Critical Care Research Group, Southampton NIHR Biomedical Research Centre, University Hospital Southampton NHS Foundation Trust, Southampton, United Kingdom.,Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, United Kingdom
| | - Anna D Clark
- Respiratory and Critical Care Research Group, Southampton NIHR Biomedical Research Centre, University Hospital Southampton NHS Foundation Trust, Southampton, United Kingdom.,Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, United Kingdom
| | - Jérôme Santolini
- Institute for Integrative Biology of the Cell (I2BC), Biochemistry, Biophysics and Structural Biology, CEA, CNRS, Université Paris-Sud, Universite Paris-Saclay, Gif-sur-Yvette, France
| | - Alan A Jackson
- Human Nutrition, University of Southampton and University Hospital Southampton, Southampton, United Kingdom
| | - Martin Feelisch
- Respiratory and Critical Care Research Group, Southampton NIHR Biomedical Research Centre, University Hospital Southampton NHS Foundation Trust, Southampton, United Kingdom.,Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, United Kingdom
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Brain D, Plant-Hately A, Heaton B, Arshad U, David C, Hedrich C, Owen A, Liptrott NJ. Drug delivery systems as immunomodulators for therapy of infectious disease: Relevance to COVID-19. Adv Drug Deliv Rev 2021; 178:113848. [PMID: 34182016 PMCID: PMC8233062 DOI: 10.1016/j.addr.2021.113848] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2021] [Revised: 06/10/2021] [Accepted: 06/22/2021] [Indexed: 02/07/2023]
Abstract
The emergence of SARS-CoV-2, and the ensuing global pandemic, has resulted in an unprecedented response to identify therapies that can limit uncontrolled inflammation observed in patients with moderate to severe COVID-19. The immune pathology behind COVID-19 is complex and involves the activation and interaction of multiple systems including, but not limited to, complement, inflammasomes, endothelial as well as innate and adaptive immune cells to bring about a convoluted profile of inflammation, coagulation and tissue damage. To date, therapeutic approaches have focussed on inhibition of coagulation, untargeted immune suppression and/or cytokine-directed blocking agents. Regardless of recently achieved improvements in individual patient outcomes and survival rates, improved and focussed approaches targeting individual systems involved is needed to further improve prognosis and wellbeing. This review summarizes the current understanding of molecular and cellular systems involved in the pathophysiology of COVID-19, and their contribution to pathogen clearance and damage to then discuss possible therapeutic options involving immunomodulatory drug delivery systems as well as summarising the complex interplay between them.
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Affiliation(s)
- Danielle Brain
- Immunocompatibility Group, Department of Pharmacology and Therapeutics, Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool, UK; Centre of Excellence for Long-acting Therapeutics (CELT), Department of Pharmacology and Therapeutics, Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool, UK
| | - Alex Plant-Hately
- Immunocompatibility Group, Department of Pharmacology and Therapeutics, Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool, UK; Centre of Excellence for Long-acting Therapeutics (CELT), Department of Pharmacology and Therapeutics, Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool, UK
| | - Bethany Heaton
- Immunocompatibility Group, Department of Pharmacology and Therapeutics, Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool, UK; Centre of Excellence for Long-acting Therapeutics (CELT), Department of Pharmacology and Therapeutics, Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool, UK
| | - Usman Arshad
- Centre of Excellence for Long-acting Therapeutics (CELT), Department of Pharmacology and Therapeutics, Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool, UK
| | - Christopher David
- Immunocompatibility Group, Department of Pharmacology and Therapeutics, Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool, UK; Centre of Excellence for Long-acting Therapeutics (CELT), Department of Pharmacology and Therapeutics, Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool, UK
| | - Christian Hedrich
- Department of Women's & Children's Health, Institute of Life Course and Medical Sciences, University of Liverpool, Liverpool, UK; Department of Rheumatology, Alder Hey Children's NHS Foundation Trust, Liverpool, UK
| | - Andrew Owen
- Centre of Excellence for Long-acting Therapeutics (CELT), Department of Pharmacology and Therapeutics, Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool, UK
| | - Neill J Liptrott
- Immunocompatibility Group, Department of Pharmacology and Therapeutics, Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool, UK; Centre of Excellence for Long-acting Therapeutics (CELT), Department of Pharmacology and Therapeutics, Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool, UK.
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Alghamdi HA, Attique SA, Yan W, Arooj A, Albulym O, Zhu D, Bilal M, Nawaz MZ. Repurposing the inhibitors of COVID-19 key proteins through molecular docking approach. Process Biochem 2021; 110:216-222. [PMID: 34421325 PMCID: PMC8367655 DOI: 10.1016/j.procbio.2021.08.015] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/21/2021] [Revised: 08/10/2021] [Accepted: 08/13/2021] [Indexed: 11/30/2022]
Abstract
The severe acute respiratory syndrome coronavirus 2, famous as COVID-19, has recently emerged as a novel virus and imposed an unrecoverable loss to global health and the economy. At present, no effective drug against COVID-19 is available and currently available viral drugs targeting the viral key proteins of related RNA viruses have been found ineffective against COVID-19. This study evaluated the inhibitors of the viral proteases and other structural proteins, including Mpro (Main protease), RdRp (RNA-dependent RNA polymerase), and spike glycoprotein from synthetic and herbal sources. The molecular docking-based approach was used to identify and evaluate the putative inhibitors of key proteins involved in viral replication and survival. Furthermore, the pharmaceutical properties of these inhibitors were explored to predict the drug suitability as a therapeutic agent against COVID-19 by considering adsorption, distribution, metabolism, and excretion (ADME) using Lipinski's rule or SwissADME. Trandolapril, Benazepril, and Moexipril were evaluated as the best non-carcinogenic and non-toxic potential inhibitors of spike glycoprotein, Mpro, and RdRp, respectively. The drugs showed significant binding affinities against the active sites of respective SARS_CoV-2 target proteins; hence, they can be used as potential therapeutic agents for the treatment of COVID-19.
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Affiliation(s)
- Huda Ahmed Alghamdi
- Department of Biology, College of Sciences, King Khalid University, Abha, 61413, Saudi Arabia
| | - Syed Awais Attique
- Department of Computer Science, University of Agriculture, Faisalabad, 38040, Pakistan
| | - Wei Yan
- Department of Marine Science, College of Marine Science and Technology, China University of Geosciences, Wuhan, China
| | - Anam Arooj
- Department of Computer Science, Virtual University of Pakistan, Lahore, 54000, Pakistan
| | - Obaid Albulym
- Department of Biology, College of Sciences, King Khalid University, Abha, 61413, Saudi Arabia
| | - Daochen Zhu
- Biofuels Institute, School of the Environment and Safety Engineering, Jiangsu University, Zhenjiang, Jiangsu, 212013, China
| | - Muhammad Bilal
- School of Life Science and Food Engineering, Huaiyin Institute of Technology, Huaian, China
| | - Muhammad Zohaib Nawaz
- Department of Computer Science, University of Agriculture, Faisalabad, 38040, Pakistan
- Biofuels Institute, School of the Environment and Safety Engineering, Jiangsu University, Zhenjiang, Jiangsu, 212013, China
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Xu M, Pradhan M, Gorshkov K, Petersen JD, Shen M, Guo H, Zhu W, Klumpp-Thomas C, Michael S, Itkin M, Itkin Z, Straus MR, Zimmerberg J, Zheng W, Whittaker GR, Chen CZ. A high throughput screening assay for inhibitors of SARS-CoV-2 pseudotyped particle entry. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2021:2021.10.04.463106. [PMID: 34642691 PMCID: PMC8509088 DOI: 10.1101/2021.10.04.463106] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Indexed: 06/13/2023]
Abstract
Effective small molecule therapies to combat the SARS-CoV-2 infection are still lacking as the COVID-19 pandemic continues globally. High throughput screening assays are needed for lead discovery and optimization of small molecule SARS-CoV-2 inhibitors. In this work, we have applied viral pseudotyping to establish a cell-based SARS-CoV-2 entry assay. Here, the pseudotyped particles (PP) contain SARS-CoV-2 spike in a membrane enveloping both the murine leukemia virus (MLV) gag-pol polyprotein and luciferase reporter RNA. Upon addition of PP to HEK293-ACE2 cells, the SARS-CoV-2 spike protein binds to the ACE2 receptor on the cell surface, resulting in priming by host proteases to trigger endocytosis of these particles, and membrane fusion between the particle envelope and the cell membrane. The internalized luciferase reporter gene is then expressed in cells, resulting in a luminescent readout as a surrogate for spike-mediated entry into cells. This SARS-CoV-2 PP entry assay can be executed in a biosafety level 2 containment lab for high throughput screening. From a collection of 5,158 approved drugs and drug candidates, our screening efforts identified 7 active compounds that inhibited the SARS-CoV-2-S PP entry. Of these seven, six compounds were active against live replicating SARS-CoV-2 virus in a cytopathic effect assay. Our results demonstrated the utility of this assay in the discovery and development of SARS-CoV-2 entry inhibitors as well as the mechanistic study of anti-SARS-CoV-2 compounds. Additionally, particles pseudotyped with spike proteins from SARS-CoV-2 B.1.1.7 and B.1.351 variants were prepared and used to evaluate the therapeutic effects of viral entry inhibitors.
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Affiliation(s)
- Miao Xu
- National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Rockville, MD, 20850
| | - Manisha Pradhan
- National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Rockville, MD, 20850
| | - Kirill Gorshkov
- National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Rockville, MD, 20850
| | - Jennifer D. Petersen
- Section on Integrative Biophysics, Division of Basic and Translational Biophysics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892
| | - Min Shen
- National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Rockville, MD, 20850
| | - Hui Guo
- National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Rockville, MD, 20850
| | - Wei Zhu
- National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Rockville, MD, 20850
| | - Carleen Klumpp-Thomas
- National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Rockville, MD, 20850
| | - Sam Michael
- National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Rockville, MD, 20850
| | - Misha Itkin
- National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Rockville, MD, 20850
| | - Zina Itkin
- National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Rockville, MD, 20850
| | - Marco R. Straus
- Department of Microbiology and Immunology, College of Veterinary Medicine, Cornell University, Ithaca, NY 14853
| | - Joshua Zimmerberg
- Section on Integrative Biophysics, Division of Basic and Translational Biophysics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892
| | - Wei Zheng
- National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Rockville, MD, 20850
| | - Gary R. Whittaker
- Department of Microbiology and Immunology, College of Veterinary Medicine, Cornell University, Ithaca, NY 14853
| | - Catherine Z. Chen
- National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Rockville, MD, 20850
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Muhammed Y, Yusuf Nadabo A, Pius M, Sani B, Usman J, Anka Garba N, Mohammed Sani J, Opeyemi Olayanju B, Zeal Bala S, Garba Abdullahi M, Sambo M. SARS-CoV-2 spike protein and RNA dependent RNA polymerase as targets for drug and vaccine development: A review. BIOSAFETY AND HEALTH 2021; 3:249-263. [PMID: 34396086 PMCID: PMC8346354 DOI: 10.1016/j.bsheal.2021.07.003] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2021] [Revised: 07/04/2021] [Accepted: 07/18/2021] [Indexed: 01/18/2023] Open
Abstract
The present pandemic has posed a crisis to the economy of the world and the health sector. Therefore, the race to expand research to understand some good molecular targets for vaccine and therapeutic development for SARS-CoV-2 is inevitable. The newly discovered coronavirus 2019 (COVID-19) is a positive sense, single-stranded RNA, and enveloped virus, assigned to the beta CoV genus. The virus (SARS-CoV-2) is more infectious than the previously detected coronaviruses (MERS and SARS). Findings from many studies have revealed that S protein and RdRp are good targets for drug repositioning, novel therapeutic development (antibodies and small molecule drugs), and vaccine discovery. Therapeutics such as chloroquine, convalescent plasma, monoclonal antibodies, spike binding peptides, and small molecules could alter the ability of S protein to bind to the ACE-2 receptor, and drugs such as remdesivir (targeting SARS-CoV-2 RdRp), favipir, and emetine could prevent SASR-CoV-2 RNA synthesis. The novel vaccines such as mRNA1273 (Moderna), 3LNP-mRNAs (Pfizer/BioNTech), and ChAdOx1-S (University of Oxford/Astra Zeneca) targeting S protein have proven to be effective in combating the present pandemic. Further exploration of the potential of S protein and RdRp is crucial in fighting the present pandemic.
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Affiliation(s)
- Yusuf Muhammed
- Department of Biochemistry, Federal University, Gusau, Nigeria,Corresponding author: Department of Biochemistry, Federal University, Gusau, Nigeria
| | | | - Mkpouto Pius
- Department of Medical Genetics, University of Cambridge, CB2 1TN, United Kingdom
| | - Bashiru Sani
- Department of Microbiology, Federal University of Lafia, Nigeria
| | - Jafar Usman
- Department of Biochemistry, Federal University, Gusau, Nigeria
| | | | | | - Basit Opeyemi Olayanju
- Department of Chemistry and Biochemistry, Florida International University, FL 33199, USA
| | | | | | - Misbahu Sambo
- Department of Biochemistry, Abubakar Tafawa Balewa University Bauchi, Nigeria
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Xu T, Zheng W, Huang R. High-throughput screening assays for SARS-CoV-2 drug development: Current status and future directions. Drug Discov Today 2021; 26:2439-2444. [PMID: 34048893 PMCID: PMC8146264 DOI: 10.1016/j.drudis.2021.05.012] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2021] [Revised: 04/16/2021] [Accepted: 05/19/2021] [Indexed: 02/08/2023]
Abstract
In response to the ongoing coronavirus disease 2019 (COVID-19) pandemic, a panel of assays has been developed and applied to screen collections of approved and investigational drugs for anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) activity in a quantitative high-throughput screening (qHTS) format. In this review, we applied data-driven approaches to evaluate the ability of each assay to identify potential anti-SARS-CoV-2 leads. Multitarget assays were found to show advantages in terms of accuracy and efficiency over single-target assays, whereas target-specific assays were more suitable for investigating compound mechanisms of action. Moreover, strict filtering with counter screens might be more detrimental than beneficial in identifying true positives. Thus, developing novel HTS assays acting simultaneously against multiple targets in the SARS-CoV-2 life cycle will benefit anti-COVID-19 drug discovery.
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Hsieh WY, Lin CH, Lin TC, Lin CH, Chang HF, Tsai CH, Wu HT, Lin CS. Development and Efficacy of Lateral Flow Point-of-Care Testing Devices for Rapid and Mass COVID-19 Diagnosis by the Detections of SARS-CoV-2 Antigen and Anti-SARS-CoV-2 Antibodies. Diagnostics (Basel) 2021; 11:1760. [PMID: 34679458 PMCID: PMC8534532 DOI: 10.3390/diagnostics11101760] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2021] [Revised: 08/26/2021] [Accepted: 09/10/2021] [Indexed: 12/15/2022] Open
Abstract
The COVID-19 pandemic is an ongoing global pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in 2020-2021. COVID-19 is becoming one of the most fatal pandemics in history and brings a huge challenge to the global healthcare system. Opportune detection, confinement, and early treatment of infected cases present the first step in combating COVID-19. Diagnosis via viral nucleic acid amplification tests (NAATs) is frequently employed and considered the standard procedure. However, with an increasing urge for point-of-care tests, rapid and cheaper immunoassays are widely utilized, such as lateral flow immunoassay (LFIA), which can be used for rapid, early, and large-scale detection of SARS-CoV-2 infection. In this narrative review, the principle and technique of LFIA applied in COVID-19 antigen and antibody detection are introduced. The diagnostic sensitivity and specificity of the commercial LFIA tests are outlined and compared. Generally, LFIA antigen tests for SARS-CoV-2 are less sensitive than viral NAATs, the "gold standard" for clinical COVID-19 diagnosis. However, antigen tests can be used for rapid and mass testing in high-risk congregate housing to quickly identify people with COVID-19, implementing infection prevention and control measures, thus preventing transmission. LFIA anti-SARS-CoV-2 antibody tests, IgM and/or IgG, known as serology tests, are used for identification if a person has previously been exposed to the virus or vaccine immunization. Notably, advanced techniques, such as LFT-based CRISPR-Cas9 and surface-enhanced Raman spectroscopy (SERS), have added new dimensions to the COVID-19 diagnosis and are also discussed in this review.
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Affiliation(s)
- Wen-Yeh Hsieh
- Department of Internal Medicine, Division of Chest Medicine, Hsinchu Mackay Memorial Hospital, Hsinchu 30068, Taiwan;
| | - Cheng-Han Lin
- Department of Biological Science and Technology, National Yang Ming Chiao Tung University, Hsinchu 30068, Taiwan; (C.-H.L.); (C.-H.L.); (H.-F.C.); (C.-H.T.)
| | - Tzu-Ching Lin
- Department of Pharmacy, College of Pharmacy, Taipei Medical University, Taipei 11031, Taiwan;
| | - Chao-Hsu Lin
- Department of Biological Science and Technology, National Yang Ming Chiao Tung University, Hsinchu 30068, Taiwan; (C.-H.L.); (C.-H.L.); (H.-F.C.); (C.-H.T.)
- Department of Pediatrics, Hsinchu Mackay Memorial Hospital, Hsinchu 30071, Taiwan
| | - Hui-Fang Chang
- Department of Biological Science and Technology, National Yang Ming Chiao Tung University, Hsinchu 30068, Taiwan; (C.-H.L.); (C.-H.L.); (H.-F.C.); (C.-H.T.)
- Department of Internal Medicine, Division of Endocrinology, Hsinchu Mackay Memorial Hospital, Hsinchu 30071, Taiwan
| | - Chin-Hung Tsai
- Department of Biological Science and Technology, National Yang Ming Chiao Tung University, Hsinchu 30068, Taiwan; (C.-H.L.); (C.-H.L.); (H.-F.C.); (C.-H.T.)
- Department of Internal Medicine, Division of Pulmonary Medicine, Tungs’ Taichung Metro Harbor Hospital, Taichung 43503, Taiwan
| | - Hsi-Tien Wu
- Department of BioAgricultural Sciences, College of Agriculture, National Chiayi University, Chiayi 60004, Taiwan;
| | - Chih-Sheng Lin
- Department of Biological Science and Technology, National Yang Ming Chiao Tung University, Hsinchu 30068, Taiwan; (C.-H.L.); (C.-H.L.); (H.-F.C.); (C.-H.T.)
- Department of Biological Science and Technology, National Chiao Tung University, Hsinchu 30068, Taiwan
- Center for Intelligent Drug Systems and Smart Bio-Devices (IDS2B), National Yang Ming Chiao Tung University, Hsinchu 30068, Taiwan
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Gajjar ND, Dhameliya TM, Shah GB. In search of RdRp and Mpro inhibitors against SARS CoV-2: Molecular docking, molecular dynamic simulations and ADMET analysis. J Mol Struct 2021; 1239:130488. [PMID: 33903778 PMCID: PMC8059878 DOI: 10.1016/j.molstruc.2021.130488] [Citation(s) in RCA: 54] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2021] [Revised: 04/08/2021] [Accepted: 04/10/2021] [Indexed: 12/16/2022]
Abstract
Corona Virus Disease 2019 (COVID-19) caused by Severe Acute Respiratory Syndrome coronavirus (SARS CoV-2) has been declared a worldwide pandemic by WHO recently. The complete understanding of the complex genomic structure of SARS CoV-2 has enabled the use of computational tools in search of SARS CoV-2 inhibitors against the multiple proteins responsible for its entry and multiplication in human cells. With this endeavor, 177 natural, anti-viral chemical entities and their derivatives, selected through the critical analysis of the literatures, were studied using pharmacophore screening followed by molecular docking against RNA dependent RNA polymerase and main protease. The identified hits have been subjected to molecular dynamic simulations to study the stability of ligand-protein complexes followed by ADMET analysis and Lipinski filters to confirm their drug likeliness. It has led to an important start point in the drug discovery and development of therapeutic agents against SARS CoV-2.
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Key Words
- 3CLpro, 3-chymotrypsin-like protease
- ACE, Angiotensin converting enzyme
- ADMET, Absorption, distribution, metabolism, excretion, and toxicity
- ASL, Atom specification language
- COVID-19, Corona virus disease-2019
- Dscore, Druggability score
- EM, Electron microscopy
- HB, Hydrogen bond
- MD simulation
- MD simulation, Molecular dynamic simulation
- Molecular docking
- Mpro
- Mpro, Main protease
- Natural products
- PLpro, Papain-like protease
- RMSD, Root mean square deviation
- RMSF, Root mean square fluctuation
- RdRP, RNA-dependent RNA polymerase
- RdRp
- RoG, Radius of gyration
- SARS CoV-2
- SARS CoV-2, Severe acute respiratory syndrome coronavirus 2
- SASA, Solvent accessible surface area
- SP, Standard precision
- WHO, World health organization
- nsp, Non-structural protein
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Global variation in SARS-CoV-2 proteome and its implication in pre-lockdown emergence and dissemination of 5 dominant SARS-CoV-2 clades. INFECTION, GENETICS AND EVOLUTION : JOURNAL OF MOLECULAR EPIDEMIOLOGY AND EVOLUTIONARY GENETICS IN INFECTIOUS DISEASES 2021; 93:104973. [PMID: 34147651 PMCID: PMC8233849 DOI: 10.1016/j.meegid.2021.104973] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/08/2021] [Revised: 05/29/2021] [Accepted: 06/15/2021] [Indexed: 02/07/2023]
Abstract
SARS-CoV-2 is currently causing major havoc worldwide with its efficient transmission and propagation. To track the emergence as well as the persistence of mutations during the early stage of the pandemic, a comparative analysis of SARS-CoV-2 whole proteome sequences has been performed by considering manually curated 31,389 whole genome sequences from 84 countries. Among the 7 highly recurring (percentage frequency≥10%) mutations (Nsp2:T85I, Nsp6:L37F, Nsp12:P323L, Spike:D614G, ORF3a:Q57H, N protein:R203K and N protein:G204R), N protein:R203K and N protein: G204R are co-occurring (dependent) mutations. Nsp12:P323L and Spike:D614G often appear simultaneously. The highly recurring Spike:D614G, Nsp12:P323L and Nsp6:L37F as well as moderately recurring (percentage frequency between ≥1 and <10%) ORF3a:G251V and ORF8:L84S mutations have led to4 major clades in addition to a clade that lacks high recurring mutations. Further, the occurrence of ORF3a:Q57H&Nsp2:T85I, ORF3a:Q57H and N protein:R203K&G204R along with Nsp12:P323L&Spike:D614G has led to 3 additional sub-clades. Similarly, occurrence of Nsp6:L37F and ORF3a:G251V together has led to the emergence of a sub-clade. Nonetheless, ORF8:L84S does not occur along with ORF3a:G251V or Nsp6:L37F. Intriguingly, ORF3a:G251V and ORF8:L84S are found to occur independent of Nsp12:P323L and Spike:D614G mutations. These clades have evolved during the early stage of the pandemic and have disseminated across several countries. Further, Nsp10 is found to be highly resistant to mutations, thus, it can be exploited for drug/vaccine development and the corresponding gene sequence can be used for the diagnosis. Concisely, the study reports the SARS-CoV-2 antigens diversity across the globe during the early stage of the pandemic and facilitates the understanding of viral evolution.
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Rehn A, Braun P, Knüpfer M, Wölfel R, Antwerpen MH, Walter MC. Catching SARS-CoV-2 by Sequence Hybridization: a Comparative Analysis. mSystems 2021; 6:e0039221. [PMID: 34342536 PMCID: PMC8407296 DOI: 10.1128/msystems.00392-21] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2021] [Accepted: 07/12/2021] [Indexed: 11/20/2022] Open
Abstract
Controlling and monitoring the still ongoing severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic regarding geographical distribution, evolution, and emergence of new mutations of the SARS-CoV-2 virus is only possible due to continuous next-generation sequencing (NGS) and sharing sequence data worldwide. Efficient sequencing strategies enable the retrieval of increasing numbers of high-quality, full-length genomes and are, hence, indispensable. Two opposed enrichment methods, tiling multiplex PCR and sequence hybridization by bait capture, have been established for SARS-CoV-2 sequencing and are both frequently used, depending on the quality of the patient sample and the question at hand. Here, we focused on the evaluation of the sequence hybridization method by studying five commercially available sequence capture bait panels with regard to sensitivity and capture efficiency. We discovered the SARS-CoV-2-specific panel of Twist Bioscience to be the most efficient panel, followed by two respiratory panels from Twist Bioscience and Illumina, respectively. Our results provide on the one hand a decision basis for the sequencing community including a computation for using the full capacity of the flow cell and on the other hand potential improvements for the manufacturers. IMPORTANCE Sequencing the genomes of the circulating SARS-CoV-2 strains is the only way to monitor the viral spread and evolution of the virus. Two different approaches, namely, tiling multiplex PCR and sequence hybridization by bait capture, are commonly used to fulfill this task. This study describes for the first time a combined approach of droplet digital PCR (ddPCR) and NGS to evaluate five commercially available sequence capture panels targeting SARS-CoV-2. In doing so, we were able to determine the most sensitive and efficient capture panel, distinguish the mode of action of the various bait panels, and compute the number of read pairs needed to recover a high-quality full-length genome. By calculating the minimum number of read pairs needed, we are providing optimized flow cell loading conditions for all sequencing laboratories worldwide that are striving for maximizing sequencing output and simultaneously minimizing time, costs, and sequencing resources.
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Affiliation(s)
| | - Peter Braun
- Bundeswehr Institute of Microbiology, Munich, Germany
| | - Mandy Knüpfer
- Bundeswehr Institute of Microbiology, Munich, Germany
| | - Roman Wölfel
- Bundeswehr Institute of Microbiology, Munich, Germany
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Muratov EN, Amaro R, Andrade CH, Brown N, Ekins S, Fourches D, Isayev O, Kozakov D, Medina-Franco JL, Merz KM, Oprea TI, Poroikov V, Schneider G, Todd MH, Varnek A, Winkler DA, Zakharov AV, Cherkasov A, Tropsha A. A critical overview of computational approaches employed for COVID-19 drug discovery. Chem Soc Rev 2021; 50:9121-9151. [PMID: 34212944 PMCID: PMC8371861 DOI: 10.1039/d0cs01065k] [Citation(s) in RCA: 116] [Impact Index Per Article: 29.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2021] [Indexed: 01/18/2023]
Abstract
COVID-19 has resulted in huge numbers of infections and deaths worldwide and brought the most severe disruptions to societies and economies since the Great Depression. Massive experimental and computational research effort to understand and characterize the disease and rapidly develop diagnostics, vaccines, and drugs has emerged in response to this devastating pandemic and more than 130 000 COVID-19-related research papers have been published in peer-reviewed journals or deposited in preprint servers. Much of the research effort has focused on the discovery of novel drug candidates or repurposing of existing drugs against COVID-19, and many such projects have been either exclusively computational or computer-aided experimental studies. Herein, we provide an expert overview of the key computational methods and their applications for the discovery of COVID-19 small-molecule therapeutics that have been reported in the research literature. We further outline that, after the first year the COVID-19 pandemic, it appears that drug repurposing has not produced rapid and global solutions. However, several known drugs have been used in the clinic to cure COVID-19 patients, and a few repurposed drugs continue to be considered in clinical trials, along with several novel clinical candidates. We posit that truly impactful computational tools must deliver actionable, experimentally testable hypotheses enabling the discovery of novel drugs and drug combinations, and that open science and rapid sharing of research results are critical to accelerate the development of novel, much needed therapeutics for COVID-19.
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Affiliation(s)
- Eugene N. Muratov
- UNC Eshelman School of Pharmacy, University of North CarolinaChapel HillNCUSA
| | - Rommie Amaro
- University of California in San DiegoSan DiegoCAUSA
| | | | | | - Sean Ekins
- Collaborations PharmaceuticalsRaleighNCUSA
| | - Denis Fourches
- Department of Chemistry, North Carolina State UniversityRaleighNCUSA
| | - Olexandr Isayev
- Department of Chemistry, Carnegie Melon UniversityPittsburghPAUSA
| | - Dima Kozakov
- Department of Applied Mathematics and Statistics, Stony Brook UniversityStony BrookNYUSA
| | | | - Kenneth M. Merz
- Department of Chemistry, Michigan State UniversityEast LansingMIUSA
| | - Tudor I. Oprea
- Department of Internal Medicine and UNM Comprehensive Cancer Center, University of New Mexico, AlbuquerqueNMUSA
- Department of Rheumatology and Inflammation Research, Gothenburg UniversitySweden
- Novo Nordisk Foundation Center for Protein Research, University of CopenhagenDenmark
| | | | - Gisbert Schneider
- Institute of Pharmaceutical Sciences, Swiss Federal Institute of TechnologyZurichSwitzerland
| | | | - Alexandre Varnek
- Department of Chemistry, University of StrasbourgStrasbourgFrance
- Institute for Chemical Reaction Design and Discovery (WPI-ICReDD), Hokkaido UniversitySapporoJapan
| | - David A. Winkler
- Monash Institute of Pharmaceutical Sciences, Monash UniversityMelbourneVICAustralia
- School of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe UniversityBundooraAustralia
- School of Pharmacy, University of NottinghamNottinghamUK
| | | | - Artem Cherkasov
- Vancouver Prostate Centre, University of British ColumbiaVancouverBCCanada
| | - Alexander Tropsha
- UNC Eshelman School of Pharmacy, University of North CarolinaChapel HillNCUSA
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48
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Hasan M, Parvez MSA, Azim KF, Imran MAS, Raihan T, Gulshan A, Muhit S, Akhand RN, Ahmed SSU, Uddin MB. Main protease inhibitors and drug surface hotspots for the treatment of COVID-19: A drug repurposing and molecular docking approach. Biomed Pharmacother 2021; 140:111742. [PMID: 34052565 PMCID: PMC8130501 DOI: 10.1016/j.biopha.2021.111742] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2021] [Revised: 05/07/2021] [Accepted: 05/13/2021] [Indexed: 12/14/2022] Open
Abstract
Here, drug repurposing and molecular docking were employed to screen approved MPP inhibitors and their derivatives to suggest a specific therapeutic agent for the treatment of COVID-19. The approved MPP inhibitors against HIV and HCV were prioritized, while RNA dependent RNA Polymerase (RdRp) inhibitor remdesivir including Favipiravir, alpha-ketoamide were studied as control groups. The target drug surface hotspot was also investigated through the molecular docking technique. Molecular dynamics was performed to determine the binding stability of docked complexes. Absorption, distribution, metabolism, and excretion analysis was conducted to understand the pharmacokinetics and drug-likeness of the screened MPP inhibitors. The results of the study revealed that Paritaprevir (-10.9 kcal/mol) and its analog (CID 131982844) (-16.3 kcal/mol) showed better binding affinity than the approved MPP inhibitors compared in this study, including remdesivir, Favipiravir, and alpha-ketoamide. A comparative study among the screened putative MPP inhibitors revealed that the amino acids T25, T26, H41, M49, L141, N142, G143, C145, H164, M165, E166, D187, R188, and Q189 are at potentially critical positions for being surface hotspots in the MPP of SARS-CoV-2. The top 5 predicted drugs (Paritaprevir, Glecaprevir, Nelfinavir, and Lopinavir) and the topmost analog showed conformational stability in the active site of the SARS-CoV-2 MP protein. The study also suggested that Paritaprevir and its analog (CID 131982844) might be effective against SARS-CoV-2. The current findings are limited to in silico analysis and lack in vivo efficacy testing; thus, we strongly recommend a quick assessment of Paritaprevir and its analog (CID 131982844) in a clinical trial.
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Affiliation(s)
- Mahmudul Hasan
- Department of Pharmaceuticals and Industrial Biotechnology, Sylhet Agricultural University, Sylhet 3100, Bangladesh
| | - Md Sorwer Alam Parvez
- Department of Genetic Engineering and Biotechnology, Shahjalal University of Science and Technology, Sylhet 3114, Bangladesh
| | - Kazi Faizul Azim
- Department of Microbial Biotechnology, Sylhet Agricultural University, Sylhet 3100, Bangladesh
| | - Md Abdus Shukur Imran
- Department of Pharmaceuticals and Industrial Biotechnology, Sylhet Agricultural University, Sylhet 3100, Bangladesh
| | - Topu Raihan
- Department of Genetic Engineering and Biotechnology, Shahjalal University of Science and Technology, Sylhet 3114, Bangladesh
| | - Airin Gulshan
- Faculty of Biotechnology and Genetic Engineering, Sylhet Agricultural University, Sylhet 3100, Bangladesh
| | - Samuel Muhit
- Department of Epidemiology and Public Health, Sylhet Agricultural University, Sylhet 3100, Bangladesh
| | - Rubaiat Nazneen Akhand
- Department of Biochemistry and Chemistry, Sylhet Agricultural University, Sylhet 3100, Bangladesh
| | - Syed Sayeem Uddin Ahmed
- Department of Epidemiology and Public Health, Sylhet Agricultural University, Sylhet 3100, Bangladesh.
| | - Md Bashir Uddin
- Department of Medicine, Sylhet Agricultural University, Sylhet 3100, Bangladesh.
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49
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Brosey CA, Houl JH, Katsonis P, Balapiti-Modarage LPF, Bommagani S, Arvai A, Moiani D, Bacolla A, Link T, Warden LS, Lichtarge O, Jones DE, Ahmed Z, Tainer JA. Targeting SARS-CoV-2 Nsp3 macrodomain structure with insights from human poly(ADP-ribose) glycohydrolase (PARG) structures with inhibitors. PROGRESS IN BIOPHYSICS AND MOLECULAR BIOLOGY 2021; 163:171-186. [PMID: 33636189 PMCID: PMC7901392 DOI: 10.1016/j.pbiomolbio.2021.02.002] [Citation(s) in RCA: 42] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/16/2020] [Revised: 01/25/2021] [Accepted: 02/10/2021] [Indexed: 01/08/2023]
Abstract
Arrival of the novel SARS-CoV-2 has launched a worldwide effort to identify both pre-approved and novel therapeutics targeting the viral proteome, highlighting the urgent need for efficient drug discovery strategies. Even with effective vaccines, infection is possible, and at-risk populations would benefit from effective drug compounds that reduce the lethality and lasting damage of COVID-19 infection. The CoV-2 MacroD-like macrodomain (Mac1) is implicated in viral pathogenicity by disrupting host innate immunity through its mono (ADP-ribosyl) hydrolase activity, making it a prime target for antiviral therapy. We therefore solved the structure of CoV-2 Mac1 from non-structural protein 3 (Nsp3) and applied structural and sequence-based genetic tracing, including newly determined A. pompejana MacroD2 and GDAP2 amino acid sequences, to compare and contrast CoV-2 Mac1 with the functionally related human DNA-damage signaling factor poly (ADP-ribose) glycohydrolase (PARG). Previously, identified targetable features of the PARG active site allowed us to develop a pharmacologically useful PARG inhibitor (PARGi). Here, we developed a focused chemical library and determined 6 novel PARGi X-ray crystal structures for comparative analysis. We applied this knowledge to discovery of CoV-2 Mac1 inhibitors by combining computation and structural analysis to identify PARGi fragments with potential to bind the distal-ribose and adenosyl pockets of the CoV-2 Mac1 active site. Scaffold development of these PARGi fragments has yielded two novel compounds, PARG-345 and PARG-329, that crystallize within the Mac1 active site, providing critical structure-activity data and a pathway for inhibitor optimization. The reported structural findings demonstrate ways to harness our PARGi synthesis and characterization pipeline to develop CoV-2 Mac1 inhibitors targeting the ADP-ribose active site. Together, these structural and computational analyses reveal a path for accelerating development of antiviral therapeutics from pre-existing drug optimization pipelines.
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Affiliation(s)
- Chris A Brosey
- Department of Molecular and Cellular Oncology, M. D. Anderson Cancer Center, Houston, TX, 77030, USA.
| | - Jerry H Houl
- Department of Molecular and Cellular Oncology, M. D. Anderson Cancer Center, Houston, TX, 77030, USA
| | - Panagiotis Katsonis
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, 77030, USA
| | | | - Shobanbabu Bommagani
- Department of Pharmaceutical Sciences, University of Arkansas for Medical Sciences, Little Rock, AR, 72205, USA
| | - Andy Arvai
- Integrative Structural & Computational Biology, The Scripps Research Institute, La Jolla, CA, 92037, USA
| | - Davide Moiani
- Department of Molecular and Cellular Oncology, M. D. Anderson Cancer Center, Houston, TX, 77030, USA
| | - Albino Bacolla
- Department of Molecular and Cellular Oncology, M. D. Anderson Cancer Center, Houston, TX, 77030, USA
| | - Todd Link
- Department of Molecular and Cellular Oncology, M. D. Anderson Cancer Center, Houston, TX, 77030, USA
| | - Leslie S Warden
- Department of Molecular and Cellular Oncology, M. D. Anderson Cancer Center, Houston, TX, 77030, USA
| | - Olivier Lichtarge
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, 77030, USA
| | - Darin E Jones
- Department of Pharmaceutical Sciences, University of Arkansas for Medical Sciences, Little Rock, AR, 72205, USA
| | - Zamal Ahmed
- Department of Molecular and Cellular Oncology, M. D. Anderson Cancer Center, Houston, TX, 77030, USA.
| | - John A Tainer
- Department of Molecular and Cellular Oncology, M. D. Anderson Cancer Center, Houston, TX, 77030, USA; Department of Cancer Biology, M.D. Anderson Cancer Center, Houston, TX, 77030, USA; Molecular Biophysics and Integrated Bioimaging, Lawrence Berkeley National Laboratory, Berkeley, CA, 94720, USA.
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50
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Hall MD, Anderson JM, Anderson A, Baker D, Bradner J, Brimacombe KR, Campbell EA, Corbett KS, Carter K, Cherry S, Chiang L, Cihlar T, de Wit E, Denison M, Disney M, Fletcher CV, Ford-Scheimer SL, Götte M, Grossman AC, Hayden FG, Hazuda DJ, Lanteri CA, Marston H, Mesecar AD, Moore S, Nwankwo JO, O’Rear J, Painter G, Singh Saikatendu K, Schiffer CA, Sheahan TP, Shi PY, Smyth HD, Sofia MJ, Weetall M, Weller SK, Whitley R, Fauci AS, Austin CP, Collins FS, Conley AJ, Davis MI. Report of the National Institutes of Health SARS-CoV-2 Antiviral Therapeutics Summit. J Infect Dis 2021; 224:S1-S21. [PMID: 34111271 PMCID: PMC8280938 DOI: 10.1093/infdis/jiab305] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
The NIH Virtual SARS-CoV-2 Antiviral Summit, held on 6 November 2020, was organized to provide an overview on the status and challenges in developing antiviral therapeutics for coronavirus disease 2019 (COVID-19), including combinations of antivirals. Scientific experts from the public and private sectors convened virtually during a live videocast to discuss severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) targets for drug discovery as well as the preclinical tools needed to develop and evaluate effective small-molecule antivirals. The goals of the Summit were to review the current state of the science, identify unmet research needs, share insights and lessons learned from treating other infectious diseases, identify opportunities for public-private partnerships, and assist the research community in designing and developing antiviral therapeutics. This report includes an overview of therapeutic approaches, individual panel summaries, and a summary of the discussions and perspectives on the challenges ahead for antiviral development.
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Affiliation(s)
- Matthew D Hall
- National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, Maryland, USA
| | - James M Anderson
- Office of the Director, National Institutes of Health, Bethesda, Maryland, USA
| | - Annaliesa Anderson
- Pfizer Vaccine Research and Development, Pfizer, Pearl River, New York, USA
| | - David Baker
- University of Washington, Seattle, Washington, USA
| | - Jay Bradner
- Novartis Institutes for BioMedical Research, Cambridge, Massachusetts, USA
| | - Kyle R Brimacombe
- National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, Maryland, USA
| | | | - Kizzmekia S Corbett
- Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA
| | | | - Sara Cherry
- University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | | | | | - Emmie de Wit
- Laboratory of Virology, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, Montana, USA
| | - Mark Denison
- Vanderbilt University, Nashville, Tennessee, USA
| | | | | | - Stephanie L Ford-Scheimer
- National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, Maryland, USA
| | | | - Abigail C Grossman
- National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, Maryland, USA
| | | | | | | | - Hilary Marston
- National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA
| | | | - Stephanie Moore
- University of Alabama at Birmingham, Birmingham, Alabama, USA
| | | | - Jules O’Rear
- US Food and Drug Administration, Silver Spring, Maryland, USA
| | | | | | - Celia A Schiffer
- University of Massachusetts Medical School, Worcester, Massachusetts, USA
| | - Timothy P Sheahan
- Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, North Carolina, USA
| | - Pei-Yong Shi
- University of Texas Medical Branch, Galveston, Texas, USA
| | - Hugh D Smyth
- University of Texas at Austin, Austin, Texas, USA
| | | | - Marla Weetall
- PTC Therapeutics, Inc, South Plainfield, New Jersey, USA
| | - Sandra K Weller
- University of Connecticut School of Medicine, Farmington, Connecticut, USA
| | - Richard Whitley
- University of Alabama at Birmingham, Birmingham, Alabama, USA
| | - Anthony S Fauci
- National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA
| | - Christopher P Austin
- National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, Maryland, USA
| | - Francis S Collins
- Office of the Director, National Institutes of Health, Bethesda, Maryland, USA
| | - Anthony J Conley
- National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA
| | - Mindy I Davis
- National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA
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