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Lusvarghi S, Vassell R, Williams B, Baha H, Neerukonda SN, Weiss CD. Capture of fusion-intermediate conformations of SARS-CoV-2 spike requires receptor binding and cleavage at either the S1/S2 or S2' site. PLoS Pathog 2025; 21:e1012808. [PMID: 40198676 PMCID: PMC12011290 DOI: 10.1371/journal.ppat.1012808] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2024] [Revised: 04/21/2025] [Accepted: 03/25/2025] [Indexed: 04/10/2025] Open
Abstract
Although structures of pre- and post-fusion conformations of SARS-CoV-2 spikes have been solved by cryo-electron microscopy, the transient spike conformations that mediate virus fusion with host cell membranes remain poorly understood. In this study, we used a peptide fusion inhibitor corresponding to the heptad repeat 2 (HR2) in the S2 transmembrane subunit of the spike to investigate fusion-intermediate conformations that involve exposure of the highly conserved heptad repeat 1 (HR1). The HR2 peptide disrupts the assembly of the HR1 and HR2 regions of the spike, which form a six-helix bundle during the transition to the post-fusion conformation. We show that binding of the spike S1 subunit to ACE2 is sufficient to induce conformational changes that allow S1 shedding and enable the HR2 peptide to bind to fusion-intermediate conformations of S2 and inhibit membrane fusion. When TMPRSS2 is also present, the peptide captures an S2' fusion intermediate though the proportion of the S2' intermediate relative to the S2 intermediate is lower in Omicron variants than pre-Omicron variants. In spikes lacking the natural S1/S2 furin cleavage site, ACE2 binding alone is not sufficient for trapping fusion intermediates, but the presence of ACE2 and TMPRSS2 allows peptide trapping of an S2' intermediate. These results indicate that, in addition to ACE2 engagement, at least one spike cleavage is needed for unwinding S2 into an HR2 peptide-sensitive, fusion-intermediate conformation. Our findings elucidate fusion-intermediate conformations of SARS-CoV-2 spike variants that expose conserved sites on spike that could be targeted by inhibitors or antibodies.
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Affiliation(s)
- Sabrina Lusvarghi
- Division of Viral Products, Office of Vaccines Research and Review, Center for Biologics Evaluation and Research, Food and Drug Administration, Silver Spring, Maryland, United States of America
| | - Russell Vassell
- Division of Viral Products, Office of Vaccines Research and Review, Center for Biologics Evaluation and Research, Food and Drug Administration, Silver Spring, Maryland, United States of America
| | - Brittany Williams
- Division of Viral Products, Office of Vaccines Research and Review, Center for Biologics Evaluation and Research, Food and Drug Administration, Silver Spring, Maryland, United States of America
| | - Haseebullah Baha
- Division of Viral Products, Office of Vaccines Research and Review, Center for Biologics Evaluation and Research, Food and Drug Administration, Silver Spring, Maryland, United States of America
| | - Sabari Nath Neerukonda
- Division of Viral Products, Office of Vaccines Research and Review, Center for Biologics Evaluation and Research, Food and Drug Administration, Silver Spring, Maryland, United States of America
| | - Carol D. Weiss
- Division of Viral Products, Office of Vaccines Research and Review, Center for Biologics Evaluation and Research, Food and Drug Administration, Silver Spring, Maryland, United States of America
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2
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Minigulov N, Boranbayev K, Bekbossynova A, Gadilgereyeva B, Filchakova O. Structural proteins of human coronaviruses: what makes them different? Front Cell Infect Microbiol 2024; 14:1458383. [PMID: 39711780 PMCID: PMC11659265 DOI: 10.3389/fcimb.2024.1458383] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2024] [Accepted: 10/17/2024] [Indexed: 12/24/2024] Open
Abstract
Following COVID-19 outbreak with its unprecedented effect on the entire world, the interest to the coronaviruses increased. The causative agent of the COVID-19, severe acute respiratory syndrome coronavirus - 2 (SARS-CoV-2) is one of seven coronaviruses that is pathogenic to humans. Others include SARS-CoV, MERS-CoV, HCoV-HKU1, HCoV-OC43, HCoV-NL63 and HCoV-229E. The viruses differ in their pathogenicity. SARS-CoV, MERS-CoV, and SARS-CoV-2 are capable to spread rapidly and cause epidemic, while HCoV-HKU1, HCoV-OC43, HCoV-NL63 and HCoV-229E cause mild respiratory disease. The difference in the viral behavior is due to structural and functional differences. All seven human coronaviruses possess four structural proteins: spike, envelope, membrane, and nucleocapsid. Spike protein with its receptor binding domain is crucial for the entry to the host cell, where different receptors on the host cell are recruited by different viruses. Envelope protein plays important role in viral assembly, and following cellular entry, contributes to immune response. Membrane protein is an abundant viral protein, contributing to the assembly and pathogenicity of the virus. Nucleocapsid protein encompasses the viral RNA into ribonucleocapsid, playing important role in viral replication. The present review provides detailed summary of structural and functional characteristics of structural proteins from seven human coronaviruses, and could serve as a practical reference when pathogenic human coronaviruses are compared, and novel treatments are proposed.
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Affiliation(s)
| | | | | | | | - Olena Filchakova
- Biology Department, School of Sciences and Humanities, Nazarbayev
University, Astana, Kazakhstan
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3
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Lubinski B, Whittaker GR. Host Cell Proteases Involved in Human Respiratory Viral Infections and Their Inhibitors: A Review. Viruses 2024; 16:984. [PMID: 38932275 PMCID: PMC11209347 DOI: 10.3390/v16060984] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2024] [Revised: 06/06/2024] [Accepted: 06/11/2024] [Indexed: 06/28/2024] Open
Abstract
Viral tropism is most commonly linked to receptor use, but host cell protease use can be a notable factor in susceptibility to infection. Here we review the use of host cell proteases by human viruses, focusing on those with primarily respiratory tropism, particularly SARS-CoV-2. We first describe the various classes of proteases present in the respiratory tract, as well as elsewhere in the body, and incorporate the targeting of these proteases as therapeutic drugs for use in humans. Host cell proteases are also linked to the systemic spread of viruses and play important roles outside of the respiratory tract; therefore, we address how proteases affect viruses across the spectrum of infections that can occur in humans, intending to understand the extrapulmonary spread of SARS-CoV-2.
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Affiliation(s)
- Bailey Lubinski
- Department of Microbiology & Immunology, College of Veterinary Medicine, Cornell University, Ithaca, NY 14850, USA;
| | - Gary R. Whittaker
- Department of Microbiology & Immunology and Public & Ecosystem Health, College of Veterinary Medicine, Cornell University, Ithaca, NY 14850, USA
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4
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Rodriguez Galvan JJ, de Vries M, Belblidia S, Fisher A, Prescott RA, Crosse KM, Mangel WF, Duerr R, Dittmann M. In-silico docking platform with serine protease inhibitor (SERPIN) structures identifies host cysteine protease targets with significance for SARS-CoV-2. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2022.11.18.517133. [PMID: 36415456 PMCID: PMC9681043 DOI: 10.1101/2022.11.18.517133] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/16/2023]
Abstract
Serine Protease Inhibitors (SERPINs) regulate protease activity in various physiological processes such as inflammation, cancer metastasis, angiogenesis, and neurodegenerative diseases. However, their potential in combating viral infections, where proteases are also crucial, remains underexplored. This is due to our limited understanding of SERPIN expression during viral-induced inflammation and of the SERPINs' full spectrum of target proteases. Here, we demonstrate widespread expression of human SERPINs in response to respiratory virus infections, both in vitro and in vivo , alongside classical antiviral effectors. Through comprehensive in-silico docking with full-length SERPIN and protease 3D structures, we confirm known inhibitors of specific proteases; more importantly, the results predict novel SERPIN-protease interactions. Experimentally, we validate the direct inhibition of key proteases essential for viral life cycles, including the SERPIN PAI-1's capability to inhibit select cysteine proteases such as cathepsin L, and the serine protease TMPRSS2. Consequently, PAI-1 suppresses spike maturation and multi-cycle SARS-CoV-2 replication. Our findings challenge conventional notions of SERPIN selectivity, underscore the power of in-silico docking for SERPIN target discovery, and offer potential therapeutic interventions targeting host proteolytic pathways to combat viruses with urgent unmet therapeutic needs. SIGNIFICANCE Serine protease inhibitors (SERPINs) play crucial roles in various physiological processes, including viral infections. However, our comprehension of the full array of proteases targeted by the SERPIN family has traditionally been limited, hindering a comprehensive understanding of their regulatory potential. We developed an in-silico docking platform to identify new SERPIN target proteases expressed in the respiratory tract, a critical viral entry portal. The platform confirmed known and predicted new targets for every SERPIN examined, shedding light on previously unrecognized patterns in SERPIN selectivity. Notably, both key proteases for SARS-CoV-2 maturation were among the newly predicted targets, which we validated experimentally. This underscores the platform's potential in uncovering targets with significance in viral infections, paving the way to define the full potential of the SERPIN family in infectious disease and beyond.
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5
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Dong W, Wang J, Tian L, Zhang J, Settles EW, Qin C, Steinken-Kollath DR, Itogawa AN, Celona KR, Yi J, Bryant M, Mead H, Jaramillo SA, Lu H, Li A, Zumwalt RE, Dadwal S, Feng P, Yuan W, Whelan SPJ, Keim PS, Barker BM, Caligiuri MA, Yu J. Factor Xa cleaves SARS-CoV-2 spike protein to block viral entry and infection. Nat Commun 2023; 14:1936. [PMID: 37024459 PMCID: PMC10079155 DOI: 10.1038/s41467-023-37336-9] [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: 08/27/2022] [Accepted: 03/13/2023] [Indexed: 04/08/2023] Open
Abstract
Serine proteases (SP), including furin, trypsin, and TMPRSS2 cleave the SARS-CoV-2 spike (S) protein, enabling the virus to enter cells. Here, we show that factor (F) Xa, an SP involved in blood coagulation, is upregulated in COVID-19 patients. In contrast to other SPs, FXa exerts antiviral activity. Mechanistically, FXa cleaves S protein, preventing its binding to ACE2, and thus blocking viral entry and infection. However, FXa is less effective against variants carrying the D614G mutation common in all pandemic variants. The anticoagulant rivaroxaban, a direct FXa inhibitor, inhibits FXa-mediated S protein cleavage and facilitates viral entry, whereas the indirect FXa inhibitor fondaparinux does not. In the lethal SARS-CoV-2 K18-hACE2 model, FXa prolongs survival yet its combination with rivaroxaban but not fondaparinux abrogates that protection. These results identify both a previously unknown function for FXa and an associated antiviral host defense mechanism against SARS-CoV-2 and suggest caution in considering direct FXa inhibitors for preventing or treating thrombotic complications in COVID-19 patients.
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Affiliation(s)
- Wenjuan Dong
- Department of Hematology & Hematopoietic Cell Transplantation, City of Hope National Medical Center, Los Angeles, CA, 91010, USA
- Hematologic Malignancies Research Institute, City of Hope National Medical Center, Los Angeles, CA, 91010, USA
| | - Jing Wang
- Department of Hematology & Hematopoietic Cell Transplantation, City of Hope National Medical Center, Los Angeles, CA, 91010, USA
- Hematologic Malignancies Research Institute, City of Hope National Medical Center, Los Angeles, CA, 91010, USA
| | - Lei Tian
- Department of Hematology & Hematopoietic Cell Transplantation, City of Hope National Medical Center, Los Angeles, CA, 91010, USA
- Hematologic Malignancies Research Institute, City of Hope National Medical Center, Los Angeles, CA, 91010, USA
| | - Jianying Zhang
- Department of Computational and Quantitative Medicine, City of Hope National Medical Center, Los Angeles, CA, 91010, USA
| | - Erik W Settles
- Pathogen and Microbiome Institute, Northern Arizona University, Flagstaff, AZ, 86011, USA
- Department of Biological Sciences, Northern Arizona University, Flagstaff, AZ, 86011, USA
| | - Chao Qin
- Section of Infection and Immunity, Herman Ostrow School of Dentistry, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, 90089, USA
| | | | - Ashley N Itogawa
- Pathogen and Microbiome Institute, Northern Arizona University, Flagstaff, AZ, 86011, USA
| | - Kimberly R Celona
- Pathogen and Microbiome Institute, Northern Arizona University, Flagstaff, AZ, 86011, USA
| | - Jinhee Yi
- Pathogen and Microbiome Institute, Northern Arizona University, Flagstaff, AZ, 86011, USA
| | - Mitchell Bryant
- Pathogen and Microbiome Institute, Northern Arizona University, Flagstaff, AZ, 86011, USA
| | - Heather Mead
- Pathogen and Microbiome Institute, Northern Arizona University, Flagstaff, AZ, 86011, USA
| | - Sierra A Jaramillo
- Pathogen and Microbiome Institute, Northern Arizona University, Flagstaff, AZ, 86011, USA
| | - Hongjia Lu
- Department of Molecular Microbiology and Immunology, Keck School of Medicine of University of Southern California, Los Angeles, CA, 90033, USA
| | - Aimin Li
- Pathology Core of Shared Resources Core, Beckman Research Institute, City of Hope National Medical Center, Los Angeles, CA, 91010, USA
| | - Ross E Zumwalt
- Department of Pathology, University of New Mexico, Albuquerque, NM, 87131, USA
| | - Sanjeet Dadwal
- Division of Infectious Diseases, Department of Medicine, City of Hope National Medical Center, Los Angeles, CA, 91010, USA
| | - Pinghui Feng
- Section of Infection and Immunity, Herman Ostrow School of Dentistry, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, 90089, USA
| | - Weiming Yuan
- Department of Molecular Microbiology and Immunology, Keck School of Medicine of University of Southern California, Los Angeles, CA, 90033, USA
| | - Sean P J Whelan
- Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, MO, 63110, USA
| | - Paul S Keim
- Pathogen and Microbiome Institute, Northern Arizona University, Flagstaff, AZ, 86011, USA
- Department of Biological Sciences, Northern Arizona University, Flagstaff, AZ, 86011, USA
| | - Bridget Marie Barker
- Pathogen and Microbiome Institute, Northern Arizona University, Flagstaff, AZ, 86011, USA
- Department of Biological Sciences, Northern Arizona University, Flagstaff, AZ, 86011, USA
| | - Michael A Caligiuri
- Department of Hematology & Hematopoietic Cell Transplantation, City of Hope National Medical Center, Los Angeles, CA, 91010, USA.
- Hematologic Malignancies Research Institute, City of Hope National Medical Center, Los Angeles, CA, 91010, USA.
- City of Hope Comprehensive Cancer Center, Los Angeles, CA, 91010, USA.
| | - Jianhua Yu
- Department of Hematology & Hematopoietic Cell Transplantation, City of Hope National Medical Center, Los Angeles, CA, 91010, USA.
- Hematologic Malignancies Research Institute, City of Hope National Medical Center, Los Angeles, CA, 91010, USA.
- City of Hope Comprehensive Cancer Center, Los Angeles, CA, 91010, USA.
- Department of Immuno-Oncology, City of Hope, Los Angeles, CA, 91010, USA.
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6
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Castillo G, Mora-Díaz JC, Breuer M, Singh P, Nelli RK, Giménez-Lirola LG. Molecular mechanisms of human coronavirus NL63 infection and replication. Virus Res 2023; 327:199078. [PMID: 36813239 PMCID: PMC9944649 DOI: 10.1016/j.virusres.2023.199078] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2022] [Revised: 02/16/2023] [Accepted: 02/17/2023] [Indexed: 02/24/2023]
Abstract
Human coronavirus NL63 (HCoV-NL63) is spread globally, causing upper and lower respiratory tract infections mainly in young children. HCoV-NL63 shares a host receptor (ACE2) with severe acute respiratory syndrome coronavirus (SARS-CoV) and SARS-CoV-2 but, unlike them, HCoV-NL63 primarily develops into self-limiting mild to moderate respiratory disease. Although with different efficiency, both HCoV-NL63 and SARS-like CoVs infect ciliated respiratory cells using ACE2 as receptor for binding and cell entry. Working with SARS-like CoVs require access to BSL-3 facilities, while HCoV-NL63 research can be performed at BSL-2 laboratories. Thus, HCoV-NL63 could be used as a safer surrogate for comparative studies on receptor dynamics, infectivity and virus replication, disease mechanism, and potential therapeutic interventions against SARS-like CoVs. This prompted us to review the current knowledge on the infection mechanism and replication of HCoV-NL63. Specifically, after a brief overview on the taxonomy, genomic organization and virus structure, this review compiles the current HCoV-NL63-related research in virus entry and replication mechanism, including virus attachment, endocytosis, genome translation, and replication and transcription. Furthermore, we reviewed cumulative knowledge on the susceptibility of different cells to HCoV-NL63 infection in vitro, which is essential for successful virus isolation and propagation, and contribute to address different scientific questions from basic science to the development and assessment of diagnostic tools, and antiviral therapies. Finally, we discussed different antiviral strategies that have been explored to suppress replication of HCoV-NL63, and other related human coronaviruses, by either targeting the virus or enhancing host antiviral mechanisms.
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Affiliation(s)
- Gino Castillo
- Department of Veterinary Diagnostic and Production Animal Medicine, Veterinary Diagnostic Laboratory, College of Veterinary Medicine, Iowa State University, 1850 Christensen Drive, Ames, IA 50011, USA
| | - Juan Carlos Mora-Díaz
- Department of Veterinary Diagnostic and Production Animal Medicine, Veterinary Diagnostic Laboratory, College of Veterinary Medicine, Iowa State University, 1850 Christensen Drive, Ames, IA 50011, USA
| | - Mary Breuer
- Department of Veterinary Diagnostic and Production Animal Medicine, Veterinary Diagnostic Laboratory, College of Veterinary Medicine, Iowa State University, 1850 Christensen Drive, Ames, IA 50011, USA
| | - Pallavi Singh
- Department of Biological Sciences, Northern Illinois University, DeKalb, IL 60115, USA
| | - Rahul K Nelli
- Department of Veterinary Diagnostic and Production Animal Medicine, Veterinary Diagnostic Laboratory, College of Veterinary Medicine, Iowa State University, 1850 Christensen Drive, Ames, IA 50011, USA
| | - Luis G Giménez-Lirola
- Department of Veterinary Diagnostic and Production Animal Medicine, Veterinary Diagnostic Laboratory, College of Veterinary Medicine, Iowa State University, 1850 Christensen Drive, Ames, IA 50011, USA.
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7
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El-Medany A, Kandoole V, Lonsdale N, Doolub G, Felekos I. In-stent Thrombosis and COVID-19 Infection: Current Insights on the Mechanistic Relationship. Curr Cardiol Rev 2023; 19:e120522204669. [PMID: 35549872 PMCID: PMC10201881 DOI: 10.2174/1573403x18666220512142019] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/03/2021] [Revised: 02/16/2022] [Accepted: 03/02/2022] [Indexed: 02/08/2023] Open
Abstract
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has been demonstrated as a major risk factor in inducing coronary stent thrombosis due to its propensity to create a pro-thrombotic state. This review explores the mechanisms that may contribute to the increased thrombosis risk seen in COVID-19. Furthermore, we discuss the patient and haematological factors that predispose to an increased risk of stent thrombosis, as well as the role of certain antiplatelet and anticoagulation therapies, including ticagrelor and enoxaparin, that may reduce the likelihood and severity of in-stent thrombosis, in SARS-CoV-2 infection. To counter the proinflammatory and pro-thrombotic state shown in COVID-19, anti-thrombotic therapy in the future may be optimised using point-of-care platelet inhibition testing and inflammation-modifying therapies. Large-scale randomised trials with long-term follow-up are increasingly necessary to assess the intersection of COVID-19 and stent optimisation as well as the reduction of stent thrombosis after drug-eluting stent (DES) implantation.
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Affiliation(s)
- Ahmed El-Medany
- Bristol Heart Institute, University Hospitals Bristol and Weston NHS Foundation Trust, Bristol, England
| | - Vanessa Kandoole
- Bristol Heart Institute, University Hospitals Bristol and Weston NHS Foundation Trust, Bristol, England
| | - Nicholas Lonsdale
- Weston General Hospital, University Hospitals Bristol and Weston NHS Foundation Trust, Bristol, UK
| | - Gemina Doolub
- Bristol Heart Institute, University Hospitals Bristol and Weston NHS Foundation Trust, Bristol, England
| | - Ioannis Felekos
- Bristol Heart Institute, University Hospitals Bristol and Weston NHS Foundation Trust, Bristol, England
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8
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Zekri-Nechar K, Zamorano-León JJ, Reche C, Giner M, López-de-Andrés A, Jiménez-García R, López-Farré AJ, Martínez-Martínez CH. Spike Protein Subunits of SARS-CoV-2 Alter Mitochondrial Metabolism in Human Pulmonary Microvascular Endothelial Cells: Involvement of Factor Xa. DISEASE MARKERS 2022; 2022:1118195. [PMID: 36438904 PMCID: PMC9699787 DOI: 10.1155/2022/1118195] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/09/2022] [Revised: 10/07/2022] [Accepted: 11/01/2022] [Indexed: 09/12/2023]
Abstract
BACKGROUND Mitochondria have been involved in host defense upon viral infections. Factor Xa (FXa), a coagulating factor, may also have influence on mitochondrial functionalities. The aim was to analyze if in human pulmonary microvascular endothelial cells (HPMEC), the SARS-CoV-2 (COVID-19) spike protein subunits, S1 and S2 (S1+S2), could alter mitochondrial metabolism and what is the role of FXA. METHODS HPMEC were incubated with and without recombinants S1+S2 (10 nmol/L each). RESULTS In control conditions, S1+S2 failed to modify FXa expression. However, in LPS (1 μg/mL)-incubated HPMEC, S1+S2 significantly increased FXa production. LPS tended to reduce mitochondrial membrane potential with respect to control, but in higher and significant degree, it was reduced when S1+S2 were present. LPS did not significantly modify cytochrome c oxidase activity as compared with control. Addition of S1+S2 spike subunits to LPS-incubated HPMEC significantly increased cytochrome c oxidase activity with respect to control. Lactate dehydrogenase activity was also increased by S1+S2 with respect to control and LPS alone. Protein expression level of uncoupled protein-2 (UCP-2) was markedly expressed when S1+S2 were added together to LPS. Rivaroxaban (50 nmol/L), a specific FXa inhibitor, significantly reduced all the above-mentioned alterations induced by S1+S2 including UCP-2 expression. CONCLUSIONS In HPMEC undergoing to preinflammatory condition, COVID-19 S1+S2 spike subunits promoted alterations in mitochondria metabolism suggesting a shift from aerobic towards anaerobic metabolism that was accompanied of high FXa production. Rivaroxaban prevented all the mitochondrial metabolic changes mediated by the present COVID-19 S1 and S2 spike subunits suggesting the involvement of endogenous FXa.
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Affiliation(s)
| | - José J. Zamorano-León
- Public Health and Maternal, Child Health Department, School of Medicine, Universidad Complutense, Madrid, Spain
- IdISSC, Madrid, Spain
| | - Carmen Reche
- Gomez Ulla Central Defense Hospital, Madrid, Spain
| | - Manel Giner
- Surgical Departments, School of Medicine, Universidad Complutense, Madrid, Spain
| | - Ana López-de-Andrés
- Public Health and Maternal, Child Health Department, School of Medicine, Universidad Complutense, Madrid, Spain
- IdISSC, Madrid, Spain
| | - Rodrigo Jiménez-García
- Public Health and Maternal, Child Health Department, School of Medicine, Universidad Complutense, Madrid, Spain
- IdISSC, Madrid, Spain
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9
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Chan SW. Fusion assays for screening of fusion inhibitors targeting SARS-CoV-2 entry and syncytia formation. Front Pharmacol 2022; 13:1007527. [PMID: 36438831 PMCID: PMC9691968 DOI: 10.3389/fphar.2022.1007527] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2022] [Accepted: 10/19/2022] [Indexed: 08/30/2023] Open
Abstract
Virus fusion process is evolutionarily conserved and provides a promising pan-viral target. Cell-cell fusion leads to syncytial formation and has implications in pathogenesis, virus spread and immune evasion. Drugs that target these processes can be developed into anti-virals. Here, we have developed sensitive, rapid, adaptable fusion reporter gene assays as models for plasma membrane and alternative fusion pathways as well as syncytial fusion in the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and have confirmed their specificity using neutralizing antibodies and specific protease inhibitors. The fusion report gene assays are more sensitive and unbiased than morphological fusion assay. The fusion assays can differentiate between transmembrane serine protease 2 (TMPRSS2)-dependency in TMPRSS2(+) cells and trypsin-dependency in angiotensin-converting enzyme 2 (ACE2)(+)TMPRSS2(-) cells. Moreover, we have identified putative novel fusion processes that are triggered by an acidic pH with and without trypsin. Coupled with morphological fusion criteria, we have found that syncytia formation is enhanced by TMPRSS2 or trypsin. By testing against our top drug hits previously shown to inhibit SARS-CoV-2 pseudovirus infection, we have identified several fusion inhibitors including structurally related lopsided kite-shaped molecules. Our results have important implications in the development of universal blockers and synergistic therapeutics and the small molecule inhibitors can provide important tools in elucidating the fusion process.
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Affiliation(s)
- Shiu-Wan Chan
- Faculty of Biology, Medicine and Health, School of Biological Sciences, The University of Manchester, Manchester, United Kingdom
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10
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The Mechanisms of Zinc Action as a Potent Anti-Viral Agent: The Clinical Therapeutic Implication in COVID-19. Antioxidants (Basel) 2022; 11:antiox11101862. [PMID: 36290585 PMCID: PMC9598180 DOI: 10.3390/antiox11101862] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2022] [Revised: 09/14/2022] [Accepted: 09/16/2022] [Indexed: 11/17/2022] Open
Abstract
The pandemic of COVID-19 was caused by a novel coronavirus termed as SARS-CoV2 and is still ongoing with high morbidity and mortality rates in the whole world. The pathogenesis of COVID-19 is highly linked with over-active immune and inflammatory responses, leading to activated cytokine storm, which contribute to ARDS with worsen outcome. Currently, there is no effective therapeutic drug for the treatment of COVID-19. Zinc is known to act as an immune modulator, which plays an important role in immune defense system. Recently, zinc has been widely considered as an anti-inflammatory and anti-oxidant agent. Accumulating numbers of studies have revealed that zinc plays an important role in antiviral immunity in several viral infections. Several early clinical trials clearly indicate that zinc treatment remarkably decreased the severity of the upper respiratory infection of rhinovirus in humans. Currently, zinc has been used for the therapeutic intervention of COVID-19 in many different clinical trials. Several clinical studies reveal that zinc treatment using a combination of HCQ and zinc pronouncedly reduced symptom score and the rates of hospital admission and mortality in COVID-19 patients. These data support that zinc might act as an anti-viral agent in the addition to its anti-inflammatory and anti-oxidant properties for the adjuvant therapeutic intervention of COVID-19.
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11
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De Maio F, Rullo M, de Candia M, Purgatorio R, Lopopolo G, Santarelli G, Palmieri V, Papi M, Elia G, De Candia E, Sanguinetti M, Altomare CD. Evaluation of Novel Guanidino-Containing Isonipecotamide Inhibitors of Blood Coagulation Factors against SARS-CoV-2 Virus Infection. Viruses 2022; 14:v14081730. [PMID: 36016352 PMCID: PMC9415951 DOI: 10.3390/v14081730] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2022] [Revised: 07/29/2022] [Accepted: 08/01/2022] [Indexed: 02/02/2023] Open
Abstract
Coagulation factor Xa (fXa) and thrombin (thr) are widely expressed in pulmonary tissues, where they may catalyze, together with the transmembrane serine protease 2 (TMPRSS2), the coronaviruses spike protein (SP) cleavage and activation, thus enhancing the SP binding to ACE2 and cell infection. In this study, we evaluate in vitro the ability of approved (i.e., dabigatran and rivaroxaban) and newly synthesized isonipecotamide-based reversible inhibitors of fXa/thr (cmpds 1-3) to hinder the SARS-CoV-2 infectivity of VERO cells. Nafamostat, which is a guanidine/amidine antithrombin and antiplasmin agent, disclosed as a covalent inhibitor of TMPRSS2, was also evaluated. While dabigatran and rivaroxaban at 100 μM concentration did not show any effect on SARS-CoV-2 infection, the virus preincubation with new guanidino-containing fXa-selective inhibitors 1 and 3 did decrease viral infectivity of VERO cells at subtoxic doses. When the cells were pre-incubated with 3, a reversible nanomolar inhibitor of fXa (Ki = 15 nM) showing the best in silico docking score toward TMPRSS2 (pdb 7MEQ), the SARS-CoV-2 infectivity was completely inhibited at 100 μM (p < 0.0001), where the cytopathic effect was just about 10%. The inhibitory effects of 3 on SARS-CoV-2 infection was evident (ca. 30%) at lower concentrations (3-50 μM). The covalent TMPRSS2 and the selective inhibitor nafamostat mesylate, although showing some effect (15-20% inhibition), did not achieve statistically significant activity against SARS-CoV-2 infection in the whole range of test concentrations (3-100 μM). These findings suggest that direct inhibitors of the main serine proteases of the blood coagulation cascade may have potential in SARS-CoV-2 drug discovery. Furthermore, they prove that basic amidino-containing fXa inhibitors with a higher docking score towards TMPRSS2 may be considered hits for optimizing novel small molecules protecting guest cells from SARS-CoV-2 infection.
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Affiliation(s)
- Flavio De Maio
- Dipartimento di Scienze di Laboratorio e Infettivologiche, Fondazione Policlinico Universitario A. Gemelli IRCCS, I-00168 Rome, Italy; (F.D.M.); (G.S.); (V.P.); (M.P.)
| | - Mariagrazia Rullo
- Department of Pharmacy–Pharmaceutical Sciences, University of Bari Aldo Moro, I-70125 Bari, Italy; (M.R.); (M.d.C.); (R.P.); (G.L.)
| | - Modesto de Candia
- Department of Pharmacy–Pharmaceutical Sciences, University of Bari Aldo Moro, I-70125 Bari, Italy; (M.R.); (M.d.C.); (R.P.); (G.L.)
| | - Rosa Purgatorio
- Department of Pharmacy–Pharmaceutical Sciences, University of Bari Aldo Moro, I-70125 Bari, Italy; (M.R.); (M.d.C.); (R.P.); (G.L.)
| | - Gianfranco Lopopolo
- Department of Pharmacy–Pharmaceutical Sciences, University of Bari Aldo Moro, I-70125 Bari, Italy; (M.R.); (M.d.C.); (R.P.); (G.L.)
| | - Giulia Santarelli
- Dipartimento di Scienze di Laboratorio e Infettivologiche, Fondazione Policlinico Universitario A. Gemelli IRCCS, I-00168 Rome, Italy; (F.D.M.); (G.S.); (V.P.); (M.P.)
| | - Valentina Palmieri
- Dipartimento di Scienze di Laboratorio e Infettivologiche, Fondazione Policlinico Universitario A. Gemelli IRCCS, I-00168 Rome, Italy; (F.D.M.); (G.S.); (V.P.); (M.P.)
| | - Massimiliano Papi
- Dipartimento di Scienze di Laboratorio e Infettivologiche, Fondazione Policlinico Universitario A. Gemelli IRCCS, I-00168 Rome, Italy; (F.D.M.); (G.S.); (V.P.); (M.P.)
| | - Gabriella Elia
- Department of Veterinary Medicine, University of Bari Aldo Moro, I-70125 Bari, Italy;
| | - Erica De Candia
- Department of Translational Medicine and Surgery, Catholic University of Rome, I-00168 Rome, Italy;
| | - Maurizio Sanguinetti
- Dipartimento di Scienze di Laboratorio e Infettivologiche, Fondazione Policlinico Universitario A. Gemelli IRCCS, I-00168 Rome, Italy; (F.D.M.); (G.S.); (V.P.); (M.P.)
- Correspondence: (M.S.); (C.D.A.)
| | - Cosimo Damiano Altomare
- Department of Pharmacy–Pharmaceutical Sciences, University of Bari Aldo Moro, I-70125 Bari, Italy; (M.R.); (M.d.C.); (R.P.); (G.L.)
- Correspondence: (M.S.); (C.D.A.)
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12
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Holcomb DD, Jankowska KI, Hernandez N, Laurie K, Kames J, Hamasaki-Katagiri N, Komar AA, DiCuccio M, Kimchi-Sarfaty C. Protocol to identify host-viral protein interactions between coagulation-related proteins and their genetic variants with SARS-CoV-2 proteins. STAR Protoc 2022; 3:101648. [PMID: 36052345 PMCID: PMC9345850 DOI: 10.1016/j.xpro.2022.101648] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Here, we describe a bioinformatics pipeline that evaluates the interactions between coagulation-related proteins and genetic variants with SARS-CoV-2 proteins. This pipeline searches for host proteins that may bind to viral protein and identifies and scores the protein genetic variants to predict the disease pathogenesis in specific subpopulations. Additionally, it is able to find structurally similar motifs and identify potential binding sites within the host-viral protein complexes to unveil viral impact on regulated biological processes and/or host-protein impact on viral invasion or reproduction. For complete details on the use and execution of this protocol, please refer to Holcomb et al. (2021).
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Affiliation(s)
- David D. Holcomb
- Center for Biologics Evaluation and Research, Office of Tissues and Advanced Therapies, Division of Plasma Protein Therapeutics, Food and Drug Administration, Silver Spring, MD, USA,Corresponding author
| | - Katarzyna I. Jankowska
- Center for Biologics Evaluation and Research, Office of Tissues and Advanced Therapies, Division of Plasma Protein Therapeutics, Food and Drug Administration, Silver Spring, MD, USA
| | - Nancy Hernandez
- Center for Biologics Evaluation and Research, Office of Tissues and Advanced Therapies, Division of Plasma Protein Therapeutics, Food and Drug Administration, Silver Spring, MD, USA
| | - Kyle Laurie
- Center for Biologics Evaluation and Research, Office of Tissues and Advanced Therapies, Division of Plasma Protein Therapeutics, Food and Drug Administration, Silver Spring, MD, USA
| | - Jacob Kames
- Center for Biologics Evaluation and Research, Office of Tissues and Advanced Therapies, Division of Plasma Protein Therapeutics, Food and Drug Administration, Silver Spring, MD, USA
| | - Nobuko Hamasaki-Katagiri
- Center for Biologics Evaluation and Research, Office of Tissues and Advanced Therapies, Division of Plasma Protein Therapeutics, Food and Drug Administration, Silver Spring, MD, USA
| | - Anton A. Komar
- Center for Gene Regulation in Health and Disease, Department of Biological, Geological and Environmental Sciences, Cleveland State University, Cleveland, OH, USA
| | - Michael DiCuccio
- National Center of Biotechnology Information, National Institutes of Health, Bethesda, MD, USA
| | - Chava Kimchi-Sarfaty
- Center for Biologics Evaluation and Research, Office of Tissues and Advanced Therapies, Division of Plasma Protein Therapeutics, Food and Drug Administration, Silver Spring, MD, USA,Corresponding author
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13
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Wong AY, Tomlinson L, Brown JP, Elson W, Walker AJ, Schultze A, Morton CE, Evans D, Inglesby P, MacKenna B, Bhaskaran K, Rentsch CT, Powell E, Williamson E, Croker R, Bacon S, Hulme W, Bates C, Curtis HJ, Mehrkar A, Cockburn J, McDonald HI, Mathur R, Wing K, Forbes H, Eggo RM, Evans SJ, Smeeth L, Goldacre B, Douglas IJ. Association between oral anticoagulants and COVID-19-related outcomes: a population-based cohort study. Br J Gen Pract 2022; 72:e456-e463. [PMID: 35440465 PMCID: PMC9037187 DOI: 10.3399/bjgp.2021.0689] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2021] [Accepted: 02/06/2022] [Indexed: 11/09/2022] Open
Abstract
BACKGROUND Early evidence has shown that anticoagulant reduces the risk of thrombotic events in those infected with COVID-19. However, evidence of the role of routinely prescribed oral anticoagulants (OACs) in COVID-19 outcomes is limited. AIM To investigate the association between OACs and COVID-19 outcomes in those with atrial fibrillation and a CHA2DS2-VASc score of 2. DESIGN AND SETTING On behalf of NHS England, a population-based cohort study was conducted. METHOD The study used primary care data and pseudonymously-linked SARS-CoV-2 antigen testing data, hospital admissions, and death records from England. Cox regression was used to estimate hazard ratios (HRs) for COVID-19 outcomes comparing people with current OAC use versus non-use, accounting for age, sex, comorbidities, other medications, deprivation, and general practice. RESULTS Of 71 103 people with atrial fibrillation and a CHA2DS2-VASc score of 2, there were 52 832 current OAC users and 18 271 non-users. No difference in risk of being tested for SARS-CoV-2 was associated with current use (adjusted HR [aHR] 0.99, 95% confidence interval [CI] = 0.95 to 1.04) versus non-use. A lower risk of testing positive for SARS-CoV-2 (aHR 0.77, 95% CI = 0.63 to 0.95) and a marginally lower risk of COVID-19-related death (aHR, 0.74, 95% CI = 0.53 to 1.04) were associated with current use versus non-use. CONCLUSION Among those at low baseline stroke risk, people receiving OACs had a lower risk of testing positive for SARS-CoV-2 and severe COVID-19 outcomes than non-users; this might be explained by a causal effect of OACs in preventing severe COVID-19 outcomes or unmeasured confounding, including more cautious behaviours leading to reduced infection risk.
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Affiliation(s)
- Angel Ys Wong
- Faculty of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine, London
| | - Laurie Tomlinson
- Faculty of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine, London
| | - Jeremy P Brown
- Faculty of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine, London
| | - William Elson
- Faculty of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine, London
| | - Alex J Walker
- The DataLab, Nuffield Department of Primary Care Health Sciences, University of Oxford, Oxford
| | - Anna Schultze
- Faculty of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine, London
| | - Caroline E Morton
- The DataLab, Nuffield Department of Primary Care Health Sciences, University of Oxford, Oxford
| | - David Evans
- The DataLab, Nuffield Department of Primary Care Health Sciences, University of Oxford, Oxford
| | - Peter Inglesby
- The DataLab, Nuffield Department of Primary Care Health Sciences, University of Oxford, Oxford
| | - Brian MacKenna
- The DataLab, Nuffield Department of Primary Care Health Sciences, University of Oxford, Oxford
| | - Krishnan Bhaskaran
- Faculty of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine, London
| | - Christopher T Rentsch
- Faculty of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine, London
| | - Emma Powell
- Faculty of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine, London
| | - Elizabeth Williamson
- Faculty of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine, London
| | - Richard Croker
- The DataLab, Nuffield Department of Primary Care Health Sciences, University of Oxford, Oxford
| | - Seb Bacon
- The DataLab, Nuffield Department of Primary Care Health Sciences, University of Oxford, Oxford
| | - William Hulme
- The DataLab, Nuffield Department of Primary Care Health Sciences, University of Oxford, Oxford
| | | | - Helen J Curtis
- The DataLab, Nuffield Department of Primary Care Health Sciences, University of Oxford, Oxford
| | - Amir Mehrkar
- The DataLab, Nuffield Department of Primary Care Health Sciences, University of Oxford, Oxford
| | | | - Helen I McDonald
- Faculty of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine, London and NIHR Health Protection Research Unit (HPRU) in Immunisation, London School of Hygiene and Tropical Medicine, London
| | - Rohini Mathur
- Faculty of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine, London
| | - Kevin Wing
- Faculty of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine, London
| | | | - Rosalind M Eggo
- Faculty of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine, London
| | - Stephen Jw Evans
- Faculty of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine, London
| | - Liam Smeeth
- Faculty of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine, London and NIHR Health Protection Research Unit (HPRU) in Immunisation, London School of Hygiene and Tropical Medicine, London
| | - Ben Goldacre
- The DataLab, Nuffield Department of Primary Care Health Sciences, University of Oxford, Oxford
| | - Ian J Douglas
- Faculty of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine, London
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14
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Plášek J, Gumulec J, Máca J, Škarda J, Procházka V, Grézl T, Václavík J. COVID-19 associated coagulopathy: Mechanisms and host-directed treatment. Am J Med Sci 2022; 363:465-475. [PMID: 34752741 PMCID: PMC8576106 DOI: 10.1016/j.amjms.2021.10.012] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2021] [Revised: 08/22/2021] [Accepted: 10/21/2021] [Indexed: 01/08/2023]
Abstract
Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) is associated with specific coagulopathy that frequently occurs during the different phases of coronavirus disease 2019 (COVID-19) and can result in thrombotic complications and/or death. This COVID-19-associated coagulopathy (CAC) exhibits some of the features associated with thrombotic microangiopathy, particularly complement-mediated hemolytic-uremic syndrome. In some cases, due to the anti-phospholipid antibodies, CAC resembles catastrophic anti-phospholipid syndrome. In other patients, it exhibits features of hemophagocytic syndrome. CAC is mainly identified by: increases in fibrinogen, D-dimers, and von Willebrand factor (released from activated endothelial cells), consumption of a disintegrin and metalloproteinase with thrombospondin type 1 motifs, member 13 (ADAMTS13), over activated and dysregulated complement, and elevated plasma cytokine levels. CAC manifests as both major cardiovascular and/or cerebrovascular events and dysfunctional microcirculation, which leads to multiple organ damage. It is not clear whether the mainstay of COVID-19 is complement overactivation, cytokine/chemokine activation, or a combination of these activities. Available data have suggested that non-critically ill hospitalized patients should be administered full-dose heparin. In critically ill, full dose heparin treatment is discouraged due to higher mortality rate. In addition to anti-coagulation, four different host-directed therapeutic pathways have recently emerged that influence CAC: (1) Anti-von Willebrand factor monoclonal antibodies; (2) activated complement C5a inhibitors; (3) recombinant ADAMTS13; and (4) Interleukin (IL)-1 and IL-6 antibodies. Moreover, neutralizing monoclonal antibodies against the virus surface protein have been tested. However, the role of antiplatelet treatment remains unclear for patients with COVID-19.
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Affiliation(s)
- Jiří Plášek
- Department of Internal Medicine and Cardiology, University Hospital Ostrava, Ostrava, Czech Republic; Department of Cardiology, Institute for Clinical and Experimental Medicine, Prague, Czech Republic; Faculty of Medicine, University of Ostrava, Ostrava, Czech Republic.
| | - J Gumulec
- Department of Clinical Hematology, University Hospital of Ostrava, Ostrava, Czech Republic
| | - J Máca
- Department of Anesthesiology and Intensive Care, University Hospital Ostrava, Ostrava, Czech Republic; Medical Faculty, Institute of Physiology and Pathophysiology, University of Ostrava, Ostrava, Czech Republic
| | - J Škarda
- Institute of Clinical Pathology, University Hospital of Ostrava, Ostrava, Czech Republic; Faculty of Medicine, University of Ostrava, Ostrava, Czech Republic
| | - V Procházka
- Institute of Radiology, University Hospital of Ostrava, Ostrava, Czech Republic
| | - T Grézl
- Department of Internal Medicine and Cardiology, University Hospital Ostrava, Ostrava, Czech Republic
| | - Jan Václavík
- Department of Internal Medicine and Cardiology, University Hospital Ostrava, Ostrava, Czech Republic; Faculty of Medicine, University of Ostrava, Ostrava, Czech Republic
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15
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Souza PFN, Mesquita FP, Amaral JL, Landim PGC, Lima KRP, Costa MB, Farias IR, Belém MO, Pinto YO, Moreira HHT, Magalhaes ICL, Castelo-Branco DSCM, Montenegro RC, de Andrade CR. The spike glycoprotein of SARS-CoV-2: A review of how mutations of spike glycoproteins have driven the emergence of variants with high transmissibility and immune escape. Int J Biol Macromol 2022; 208:105-125. [PMID: 35300999 PMCID: PMC8920968 DOI: 10.1016/j.ijbiomac.2022.03.058] [Citation(s) in RCA: 39] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2021] [Revised: 03/08/2022] [Accepted: 03/10/2022] [Indexed: 12/23/2022]
Abstract
Late in 2019, SARS-CoV-2 (severe acute respiratory syndrome coronavirus-2) emerged, causing an unknown type of pneumonia today called coronaviruses disease 2019 (COVID-19). COVID-19 is still an ongoing global outbreak that has claimed and threatened many lives worldwide. Along with the fastest vaccine developed in history to fight SARS-CoV-2 came a critical problem, SARS-CoV-2. These new variants are a result of the accumulation of mutations in the sequence and structure of spike (S) glycoprotein, which is by far the most critical protein for SARS-CoV-2 to recognize cells and escape the immune system, in addition to playing a role in SARS-CoV-2 infection, pathogenicity, transmission, and evolution. In this review, we discuss mutation of S protein and how these mutations have led to new variants that are usually more transmissible and can thus mitigate the immunity produced by vaccination. Here, analysis of S protein sequences and structures from variants point out the mutations among them, how they emerge, and the behavior of S protein from each variant. This review brings details in an understandable way about how the variants of SARS-CoV-2 are a result of mutations in S protein, making them more transmissible and even more aggressive than their relatives.
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Affiliation(s)
- Pedro F N Souza
- Department of Biochemistry and Molecular Biology, Federal University of Ceará, Brazil; Drug research and Development Center, Department of Medicine, Federal University of Ceará, Brazil.
| | - Felipe P Mesquita
- Drug research and Development Center, Department of Medicine, Federal University of Ceará, Brazil
| | - Jackson L Amaral
- Department of Biochemistry and Molecular Biology, Federal University of Ceará, Brazil
| | - Patrícia G C Landim
- Department of Biochemistry and Molecular Biology, Federal University of Ceará, Brazil
| | - Karollyny R P Lima
- Department of Biochemistry and Molecular Biology, Federal University of Ceará, Brazil
| | - Marília B Costa
- Drug research and Development Center, Department of Medicine, Federal University of Ceará, Brazil
| | - Izabelle R Farias
- Drug research and Development Center, Department of Medicine, Federal University of Ceará, Brazil
| | - Mônica O Belém
- Laboratory of Translational Research, Christus University Center, Fortaleza, Ceará 60192, Brazil
| | - Yago O Pinto
- Medical Education Institution-Idomed, Canindé, Ceará, Brazil
| | | | | | - Débora S C M Castelo-Branco
- Department of Pathology and Legal Medicine, Postgraduate Program in Medical Microbiology, Group of Applied Medical Microbiology, Federal University of Ceará, Fortaleza, Ceará, Brazil
| | - Raquel C Montenegro
- Drug research and Development Center, Department of Medicine, Federal University of Ceará, Brazil
| | - Claudia R de Andrade
- Laboratory of Translational Research, Christus University Center, Fortaleza, Ceará 60192, Brazil
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16
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Ali F, Alom S, Shakya A, Ghosh SK, Singh UP, Bhat HR. Implication of in silico studies in the search for novel inhibitors against SARS-CoV-2. Arch Pharm (Weinheim) 2022; 355:e2100360. [PMID: 35244237 PMCID: PMC9073995 DOI: 10.1002/ardp.202100360] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2021] [Revised: 01/11/2022] [Accepted: 01/14/2022] [Indexed: 11/12/2022]
Abstract
Corona Virus Disease-19 (COVID-19) is a pandemic disease mainly caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). It had spread from Wuhan, China, in late 2019 and spread over 222 countries and territories all over the world. Earlier, at the very beginning of COVID-19 infection, there were no approved medicines or vaccines for combating this disease, which adversely affected a lot of individuals worldwide. Although frequent mutation leads to the generation of more deadly variants of SARS-CoV-2, researchers have developed several highly effective vaccines that were approved for emergency use by the World Health Organization (WHO), such as mRNA-1273 by Moderna, BNT162b2 by Pfizer/BioNTech, Ad26.COV2.S by Janssen, AZD1222 by Oxford/AstraZeneca, Covishield by the Serum Institute of India, BBIBP-CorV by Sinopharm, coronaVac by Sinovac, and Covaxin by Bharat Biotech, and the first US Food and Drug Administration-approved antiviral drug Veklury (remdesivir) for the treatment of COVID-19. Several waves of COVID-19 have already occurred worldwide, and good-quality vaccines and medicines should be available for ongoing as well as upcoming waves of the pandemic. Therefore, in silico studies have become an excellent tool for identifying possible ligands that could lead to the development of safer medicines or vaccines. Various phytoconstituents from plants and herbs with antiviral properties are studied further to obtain inhibitors of SARS-CoV-2. In silico screening of various molecular databases like PubChem, ZINC, Asinex Biol-Design Library, and so on has been performed extensively for finding effective ligands against targets. Herein, in silico studies carried out by various researchers are summarized so that one can easily find the best molecule for further in vitro and in vivo studies.
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Affiliation(s)
- Farak Ali
- Girijananda Chowdhury Institute of Pharmaceutical ScienceTezpur, SonitpurAssamIndia
| | - Shahnaz Alom
- Girijananda Chowdhury Institute of Pharmaceutical ScienceTezpur, SonitpurAssamIndia
| | - Anshul Shakya
- Department of Pharmaceutical SciencesDibrugarh UniversityDibrugarhAssamIndia
| | - Surajit K. Ghosh
- Department of Pharmaceutical SciencesDibrugarh UniversityDibrugarhAssamIndia
| | - Udaya P. Singh
- Drug Design & Discovery Laboratory, Department of Pharmaceutical Sciences, Sam Higginbottom University of AgricultureTechnology & SciencesAllahabadUttar PradeshIndia
| | - Hans R. Bhat
- Department of Pharmaceutical SciencesDibrugarh UniversityDibrugarhAssamIndia
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17
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Kastenhuber ER, Mercadante M, Nilsson-Payant B, Johnson JL, Jaimes JA, Muecksch F, Weisblum Y, Bram Y, Whittaker GR, tenOever BR, Schwartz RE, Chandar V, Cantley L. Coagulation factors directly cleave SARS-CoV-2 spike and enhance viral entry. eLife 2022; 11:77444. [PMID: 35294338 PMCID: PMC8942469 DOI: 10.7554/elife.77444] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2022] [Accepted: 02/22/2022] [Indexed: 11/13/2022] Open
Abstract
Coagulopathy is a significant aspect of morbidity in COVID-19 patients. The clotting cascade is propagated by a series of proteases, including factor Xa and thrombin. While certain host proteases, including TMPRSS2 and furin, are known to be important for cleavage activation of SARS-CoV-2 spike to promote viral entry in the respiratory tract, other proteases may also contribute. Using biochemical and cell-based assays, we demonstrate that factor Xa and thrombin can also directly cleave SARS-CoV-2 spike, enhancing infection at the stage of viral entry. Coagulation factors increased SARS-CoV-2 infection in human lung organoids. A drug-repurposing screen identified a subset of protease inhibitors that promiscuously inhibited spike cleavage by both transmembrane serine proteases and coagulation factors. The mechanism of the protease inhibitors nafamostat and camostat may extend beyond inhibition of TMPRSS2 to coagulation-induced spike cleavage. Anticoagulation is critical in the management of COVID-19, and early intervention could provide collateral benefit by suppressing SARS-CoV-2 viral entry. We propose a model of positive feedback whereby infection-induced hypercoagulation exacerbates SARS-CoV-2 infectivity.
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Affiliation(s)
| | - Marisa Mercadante
- Department of Medicine, Weill Cornell Medical College, New York, United States
| | - Benjamin Nilsson-Payant
- Institute of Experimental Virology, TWINCORE Zentrum für Experimentelle und Klinische Infektionsforschung GmbH, Hannover, Germany
| | - Jared L Johnson
- Department of Medicine, Weill Cornell Medical College, New York, United States
| | - Javier A Jaimes
- Department of Microbiology and Immunology, Cornell University, Ithaca, United States
| | - Frauke Muecksch
- Laboratory of Retrovirology, The Rockefeller University, New York, United States
| | - Yiska Weisblum
- Laboratory of Retrovirology, The Rockefeller University, New York, United States
| | - Yaron Bram
- Department of Medicine, Weill Cornell Medicine, New York, United States
| | - Gary R Whittaker
- Department of Microbiology and Immunology, Cornell University, Ithaca, United States
| | - Benjamin R tenOever
- Department of Microbiology, New York University Langone Medical Center, New York, United States
| | - Robert E Schwartz
- Department of Medicine, Weill Cornell Medicine, New York, United States
| | - Vasuretha Chandar
- Department of Medicine, Weill Cornell Medicine, New York, United States
| | - Lewis Cantley
- Department of Medicine, Weill Cornell Medical College, New York, United States
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18
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Papaj K, Spychalska P, Kapica P, Fischer A, Nowak J, Bzówka M, Sellner M, Lill MA, Smieško M, Góra A. Evaluation of Xa inhibitors as potential inhibitors of the SARS-CoV-2 Mpro protease. PLoS One 2022; 17:e0262482. [PMID: 35015795 PMCID: PMC8752003 DOI: 10.1371/journal.pone.0262482] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2021] [Accepted: 12/24/2021] [Indexed: 02/07/2023] Open
Abstract
Based on previous large-scale in silico screening several factor Xa inhibitors were proposed to potentially inhibit SARS-CoV-2 Mpro. In addition to their known anticoagulants activity this potential inhibition could have an additional therapeutic effect on patients with COVID-19 disease. In this study we examined the binding of the Apixaban, Betrixaban and Rivaroxaban to the SARS-CoV-2 Mpro with the use of the MicroScale Thermophoresis technique. Our results indicate that the experimentally measured binding affinity is weak and the therapeutic effect due to the SARS-CoV-2 Mpro inhibition is rather negligible.
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Affiliation(s)
- Katarzyna Papaj
- Tunneling Group, Biotechnology Centre, Silesian University of Technology, Gliwice, Poland
| | - Patrycja Spychalska
- Tunneling Group, Biotechnology Centre, Silesian University of Technology, Gliwice, Poland
| | - Patryk Kapica
- Tunneling Group, Biotechnology Centre, Silesian University of Technology, Gliwice, Poland
| | - André Fischer
- Department of Pharmaceutical Sciences, Computational Pharmacy, University of Basel, Basel, Switzerland
| | - Jakub Nowak
- Faculty of Biochemistry, Biophysics and Biotechnology, Department of Physical Biochemistry, Jagiellonian University, Krakow, Poland
| | - Maria Bzówka
- Tunneling Group, Biotechnology Centre, Silesian University of Technology, Gliwice, Poland
| | - Manuel Sellner
- Department of Pharmaceutical Sciences, Computational Pharmacy, University of Basel, Basel, Switzerland
| | - Markus A. Lill
- Department of Pharmaceutical Sciences, Computational Pharmacy, University of Basel, Basel, Switzerland
| | - Martin Smieško
- Department of Pharmaceutical Sciences, Computational Pharmacy, University of Basel, Basel, Switzerland
| | - Artur Góra
- Tunneling Group, Biotechnology Centre, Silesian University of Technology, Gliwice, Poland
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19
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Traets MJM, Nijhuis RHT, Morré SA, Ouburg S, Remijn JA, Blok BA, de Laat B, Jong E, Herder GJM, Fiolet ATL, Verweij SP. Association of genetic variations in ACE2, TIRAP and factor X with outcomes in COVID-19. PLoS One 2022; 17:e0260897. [PMID: 34995294 PMCID: PMC8740962 DOI: 10.1371/journal.pone.0260897] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2021] [Accepted: 11/18/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), can manifest with varying disease severity and mortality. Genetic predisposition influences the clinical course of infectious diseases. We investigated whether genetic polymorphisms in candidate genes ACE2, TIRAP, and factor X are associated with clinical outcomes in COVID-19. METHODS We conducted a single-centre retrospective cohort study. All patients who visited the emergency department with SARS-CoV-2 infection proven by polymerase chain reaction were included. Single nucleotide polymorphisms in ACE2 (rs2285666), TIRAP (rs8177374) and factor X (rs3211783) were assessed. The outcomes were mortality, respiratory failure and venous thromboembolism. Respiratory failure was defined as the necessity of >5 litres/minute oxygen, high flow nasal oxygen suppletion or mechanical ventilation. RESULTS Between March and April 2020, 116 patients (35% female, median age 65 [inter quartile range 55-75] years) were included and treated according to the then applicable guidelines. Sixteen patients (14%) died, 44 patients (38%) had respiratory failure of whom 23 required endotracheal intubation for mechanical ventilation, and 20 patients (17%) developed venous thromboembolism. The percentage of TIRAP polymorphism carriers in the survivor group was 28% as compared to 0% in the non-survivor group (p = 0.01, Bonferroni corrected p = 0.02). Genotype distribution of ACE2 and factor X did not differ between survivors and non-survivors. CONCLUSION This study shows that carriage of TIRAP polymorphism rs8177374 could be associated with a significantly lower mortality in COVID-19. This TIRAP polymorphism may be an important predictor in the outcome of COVID-19.
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Affiliation(s)
- Marissa J. M. Traets
- Meander Medical Centre, Department of Internal Medicine, Amersfoort, The Netherlands
| | - Roel H. T. Nijhuis
- Meander Medical Centre, Department of Medical Microbiology and Medical Immunology, Amersfoort, The Netherlands
| | - Servaas A. Morré
- Department of Medical Microbiology and Infection Control, Laboratory of Immunogenetics, Amsterdam UMC, Amsterdam, The Netherlands
- Department of Genetics and Cell Biology, Institute for Public Health Genomics, Research Institute GROW, Faculty of Health, Medicine & Life Sciences, University of Maastricht, Maastricht, The Netherlands
| | - Sander Ouburg
- Department of Medical Microbiology and Infection Control, Laboratory of Immunogenetics, Amsterdam UMC, Amsterdam, The Netherlands
| | - Jasper A. Remijn
- Meander Medical Centre, Department of Clinical Chemistry, Amersfoort, The Netherlands
| | - Bastiaan A. Blok
- Meander Medical Centre, Department of Internal Medicine, Amersfoort, The Netherlands
| | - Bas de Laat
- Synapse Research Institute, Maastricht, The Netherlands
| | - Eefje Jong
- Meander Medical Centre, Department of Internal Medicine, Amersfoort, The Netherlands
| | - Gerarda J. M. Herder
- Meander Medical Centre, Department of Pulmonary Disease, Amersfoort, The Netherlands
| | - Aernoud T. L. Fiolet
- Meander Medical Centre, Department of Internal Medicine, Amersfoort, The Netherlands
| | - Stephan P. Verweij
- Meander Medical Centre, Department of Internal Medicine, Amersfoort, The Netherlands
- Department of Respiratory Medicine, University Medical Centre Utrecht, Utrecht, The Netherlands
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20
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Proposed mechanism for rare thrombotic events after use of some Covid-19 vaccines. Med Hypotheses 2022; 159:110756. [PMID: 35002021 PMCID: PMC8722443 DOI: 10.1016/j.mehy.2021.110756] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2021] [Revised: 11/09/2021] [Accepted: 11/19/2021] [Indexed: 11/20/2022]
Abstract
Administration of AstraZeneca/Oxford and Johnson & Johnson/Janssen Covid-19 vaccines which use an adenovirus vector for DNA delivery has been associated with very rare thromboembolic complications coupled with an immune response to platelet factor 4 protein. The cause of this has not yet been identified. It is known that binding of coagulation factor proteins to the surface of some adenoviruses can protect their function. Here I propose that the thromboembolic events are caused by impairment of coagulation factor X binding to the virus capsid. The unprotected capsid then stimulates an immune response leading to platelet activation, increased thrombogenicity and formation of an antibody complex with platelet factor 4. Impaired binding of factor X may be due to an undiagnosed mutation in affected individuals. Options to test this mechanism experimentally and potential remedial actions to resolve the hazard are described. This mechanism offers a remedial route to address concerns about the safety of these vaccines, which are otherwise well-positioned to deliver global Covid-19 immunity across diverse healthcare economies.
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21
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Bertanha M, Rodrigues LDS, Mellucci Filho PL, Moroz A, Pardini MIDMC, Sobreira ML, Durigon EL, Machado RRG, Grotto RMT, de Lima MA, Nader HB, de Moraes ML, Barbosa AN, Medolago NB, Cardoso FF, Magro AJ, Carvalho CRG, de Moraes LN, Alvarado RDC, Nunes HC, de Campos GC, Grillo VTRDS, Sertorio ND, Fortaleza CMCB. Nebulized enriched heparin to treat no critical patients with Sars-Cov-2: Triple-blind clinical trial. Medicine (Baltimore) 2021; 100:e28288. [PMID: 34941114 PMCID: PMC8702290 DOI: 10.1097/md.0000000000028288] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/24/2021] [Accepted: 11/29/2021] [Indexed: 01/05/2023] Open
Abstract
BACKGROUND Coronavirus disease 2019 (COVID-19) is a viral respiratory disease that spreads rapidly, reaching pandemic status, causing the collapse of numerous health systems, and a strong economic and social impact. The treatment so far has not been well established and there are several clinical trials testing known drugs that have antiviral activity, due to the urgency that the global situation imposes. Drugs with specific mechanisms of action can take years to be discovered, while vaccines may also take a long time to be widely distributed while new virus variants emerge. Thus, drug repositioning has been shown to be a good strategy for defining new therapeutic approaches. Studies of the effect of enriched heparin in the replication of severe acute respiratory syndrome Coronavirus 2 (SARS-CoV-2) in vitro assays justify the advance for clinical tests. METHODS AND ANALYSIS A phase I/II triple-blind parallel clinical trial will be conducted. Fifty participants with radiological diagnosis of grade IIA pneumonia will be selected, which will be allocated in 2 arms. Participants allocated in Group 1 (placebo) will receive nebulized 0.9% saline. Participants allocated in Group 2 (intervention) will receive nebulized enriched heparin (2.5 mg/mL 0.9% saline). Both groups will receive the respective solutions on a 4/4 hour basis, for 7 days. The main outcomes of interest will be safety (absence of serious adverse events) and efficacy (measured by the viral load).Protocols will be filled on a daily basis, ranging from day 0 (diagnosis) until day 8.
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Affiliation(s)
- Matheus Bertanha
- Department of Surgery and Orthopedics, São Paulo State University – UNESP, Botucatu Medical School, Botucatu, SP, Brazil
- Applied Biotechnology Laboratory, Research Nucleus of Clinical Hospital, São Paulo State University – UNESP, Botucatu Medical School, Botucatu, SP, Brazil
| | - Lenize da Silva Rodrigues
- Department of Surgery and Orthopedics, São Paulo State University – UNESP, Botucatu Medical School, Botucatu, SP, Brazil
| | - Pedro Luciano Mellucci Filho
- Department of Surgery and Orthopedics, São Paulo State University – UNESP, Botucatu Medical School, Botucatu, SP, Brazil
| | - Andrei Moroz
- Department of Bioprocess and Biotechnology, São Paulo State University – UNESP, School of Pharmaceutical Sciences, Araraquara, SP, Brazil
| | - Maria Inês de Moura Campos Pardini
- Applied Biotechnology Laboratory, Research Nucleus of Clinical Hospital, São Paulo State University – UNESP, Botucatu Medical School, Botucatu, SP, Brazil
- Internal Medicine Division, São Paulo State University – UNESP, Botucatu Medical School, Botucatu, SP, Brazil
| | - Marcone Lima Sobreira
- Department of Surgery and Orthopedics, São Paulo State University – UNESP, Botucatu Medical School, Botucatu, SP, Brazil
| | - Edison Luiz Durigon
- Department of Microbiology, Institute of Biomedical Sciences, University of São Paulo – USP, São Paulo, SP, Brazil
- Scientific Platform Pasteur, University of São Paulo – USP, São Paulo, SP, Brazil
| | | | - Rejane Maria Tommasini Grotto
- Applied Biotechnology Laboratory, Research Nucleus of Clinical Hospital, São Paulo State University – UNESP, Botucatu Medical School, Botucatu, SP, Brazil
- Bioprocessing and Biotechnology Department, São Paulo State University – UNESP, School of Agriculture, Botucatu, SP, Brazil
| | - Marcelo Andrade de Lima
- Molecular & Structural Biosciences, School of Life Sciences, Keele University, Newcastle-Under-Lyme, Staffordshire, UK
| | - Helena Bonciani Nader
- Department of Biochemistry, Federal University of São Paulo – UNIFESP, São Paulo, SP, Brazil
| | - Marli Leite de Moraes
- Institute of Science and Technology, Federal University of São Paulo – UNIFESP, São José dos Campos, SP, Brazil
| | - Alexandre Naime Barbosa
- Department of Infectious Diseases, São Paulo State University – UNESP, Botucatu Medical School, Botucatu, SP, Brazil
| | - Natália Bronzatto Medolago
- Clinical Research Unit, São Paulo State University – UNESP, Botucatu Medical School, Botucatu, SP, Brazil
| | | | - Angelo José Magro
- Biosciences Institute, São Paulo State University – UNESP, Botucatu, SP, Brazil
| | | | - Leonardo Nazário de Moraes
- Applied Biotechnology Laboratory, Research Nucleus of Clinical Hospital, São Paulo State University – UNESP, Botucatu Medical School, Botucatu, SP, Brazil
- Bioprocessing and Biotechnology Department, São Paulo State University – UNESP, School of Agriculture, Botucatu, SP, Brazil
| | - Rita de Cássia Alvarado
- Applied Biotechnology Laboratory, Research Nucleus of Clinical Hospital, São Paulo State University – UNESP, Botucatu Medical School, Botucatu, SP, Brazil
| | - Helga Caputo Nunes
- Quality control laboratory, Cellavita Scientific Research, Valinhos, SP, Brazil
| | - Gustavo Constantino de Campos
- Department of Orthopedics and Traumatology, University of Campinas – UNICAMP, School of Medical Sciences, Campinas, SP, Brazil
| | | | - Nathalia Dias Sertorio
- Department of Surgery and Orthopedics, São Paulo State University – UNESP, Botucatu Medical School, Botucatu, SP, Brazil
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22
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Treatments Associated with Lower Mortality among Critically Ill COVID-19 Patients: A Retrospective Cohort Study. Anesthesiology 2021; 135:1076-1090. [PMID: 34597362 DOI: 10.1097/aln.0000000000003999] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
BACKGROUND Mortality in critically ill COVID-19 patients remains high. Although randomized controlled trials must continue to definitively evaluate treatments, further hypothesis-generating efforts to identify candidate treatments are required. This study's hypothesis was that certain treatments are associated with lower COVID-19 mortality. METHODS This was a 1-yr retrospective cohort study involving all COVID-19 patients admitted to intensive care units in six hospitals affiliated with Yale New Haven Health System from February 13, 2020, to March 4, 2021. The exposures were any COVID-19-related pharmacologic and organ support treatments. The outcome was in-hospital mortality. RESULTS This study analyzed 2,070 patients after excluding 23 patients who died within 24 h after intensive care unit admission and 3 patients who remained hospitalized on the last day of data censoring. The in-hospital mortality was 29% (593 of 2,070). Of 23 treatments analyzed, apixaban (hazard ratio, 0.42; 95% CI, 0.363 to 0.48; corrected CI, 0.336 to 0.52) and aspirin (hazard ratio, 0.72; 95% CI, 0.60 to 0.87; corrected CI, 0.54 to 0.96) were associated with lower mortality based on the multivariable analysis with multiple testing correction. Propensity score-matching analysis showed an association between apixaban treatment and lower mortality (with vs. without apixaban, 27% [96 of 360] vs. 37% [133 of 360]; hazard ratio, 0.48; 95% CI, 0.337 to 0.69) and an association between aspirin treatment and lower mortality (with vs. without aspirin, 26% [121 of 473] vs. 30% [140 of 473]; hazard ratio, 0.57; 95% CI, 0.41 to 0.78). Enoxaparin showed similar associations based on the multivariable analysis (hazard ratio, 0.82; 95% CI, 0.69 to 0.97; corrected CI, 0.61 to 1.05) and propensity score-matching analysis (with vs. without enoxaparin, 25% [87 of 347] vs. 34% [117 of 347]; hazard ratio, 0.53; 95% CI, 0.367 to 0.77). CONCLUSIONS Consistent with the known hypercoagulability in severe COVID-19, the use of apixaban, enoxaparin, or aspirin was independently associated with lower mortality in critically ill COVID-19 patients. EDITOR’S PERSPECTIVE
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23
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Islam SS, Midya S, Sinha S, Saadi SMAI. Natural medicinal plant products as an immune-boosters: A possible role to lessen the impact of Covid-19. CASE STUDIES IN CHEMICAL AND ENVIRONMENTAL ENGINEERING 2021; 4:100105. [PMID: 38620656 PMCID: PMC8096520 DOI: 10.1016/j.cscee.2021.100105] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/17/2021] [Revised: 04/21/2021] [Accepted: 04/23/2021] [Indexed: 05/27/2023]
Abstract
Transmissible Covid-19, caused by novel corona virus since last of 2019 has outspread widely until now. Where, India was the second most affected country and 3rd in mortality rate. In world ancient history, medicinal plants were played a crucial role to cure several diseases. In present study, we show some novel natural medicinal plant metabolites as the potential inhibitors against papain-like protease (PLpro), main protease (Mpro) and RNA-dependent RNA polymerase (RdRp), transmembrane proteinase Serine 2 (TMPRSS2) and angiotensin converting enzyme-2 (ACE-2) of Covid-19. Plant metabolites were having been proven to inhibit SARS-CoVs, which also actively walkable against Covid-19.
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Key Words
- ACE-2, angiotensin converting enzyme-2
- CSG, Coronavirus Study Group
- Covid-19
- Covid-19, corona virus disease-2019
- E, small envelope protein
- IC, Inhibitory concentration
- ICTV, International Committee on Taxonomy of Viruses
- M, matrix protein
- Medicinal plant
- Mpro, main protease
- N, nucleocapsid protein
- PLpro, papain-like protease
- Plant metabolites
- RBD, receptor binding domain
- RdRp, RNA-dependent RNA polymerase
- S, spike protein
- SARS-CoV
- ST, swine testicular
- TMPRSS2, transmembrane proteinase Serine 2
- WHO, world health organization
- nsps, non-structural proteins
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Affiliation(s)
- Sk Saruk Islam
- Department of Plant Pathology, Bidhan Chandra Krishi Viswavidyalaya, Mohanpur, 741235, West Bengal, India
| | - Sujoy Midya
- Department of Zoology, Raja N.L. Khan Women's College, Midnapore, West Bengal, 721102, India
| | - Sanjit Sinha
- Department of Botany and Forestry, Vidyasagar University, Midnapore, West Bengal, 721102, India
| | - Sk Md Abu Imam Saadi
- Department of Biological Sciences, Aliah University, IIA/27, New Town, Kolkata, 700160, West Bengal, India
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24
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Genomic diversity and molecular dynamics interaction on mutational variances among RB domains of SARS-CoV-2 interplay drug inactivation. INFECTION GENETICS AND EVOLUTION 2021; 97:105128. [PMID: 34752930 PMCID: PMC8571106 DOI: 10.1016/j.meegid.2021.105128] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/11/2021] [Revised: 10/16/2021] [Accepted: 10/25/2021] [Indexed: 11/24/2022]
Abstract
The scientific community has been releasing whole genomic sequences of SARS-CoV-2 to facilitate the investigation of molecular features and evolutionary history. We retrieved 36 genomes of 18 prevalent countries of Asia, Europe and America for genomic diversity and mutational analysis. Besides, we studied mutations in the RBD regions of Spike (S) proteins to analyze the drug efficiency against these mutations. In this research, phylogenenetic analysis, evolutionary modeling, substitution pattern analysis, molecular docking, dynamics simulation, etc. were performed. The genomic sequences showed >99% similarity with the reference sequence of China.TN93 + G was predicted as a best nucleotide substitution model. It was revealed that effective transition from the co-existing SARS genome to the SARS-CoV-2 and a noticeable positive selection in the SARS-CoV-2 genomes occurred. Moreover, three mutations in RBD domain, Val/ Phe367, Val/ Leu 382 and Ala/ Val522, were discovered in the genomes from Netherland, Bangladesh and the USA, respectively. Molecular docking and dynamics study showed RBD with mutation Val/Leu382 had the lowest binding affinity with remdesivir. In conclusion, the SARS-CoV-2 genomes are similar, but multiple degrees of transitions and transversions occurred. The mutations cause a significant conformational change, which are needed to be investigated during drug and vaccine development.
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25
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Kaur A, Chopra M, Bhushan M, Gupta S, Kumari P H, Sivagurunathan N, Shukla N, Rajagopal S, Bhalothia P, Sharma P, Naravula J, Suravajhala R, Gupta A, Abbasi BA, Goswami P, Singh H, Narang R, Polavarapu R, Medicherla KM, Valadi J, Kumar S A, Chaubey G, Singh KK, Bandapalli OR, Kavi Kishor PB, Suravajhala P. The Omic Insights on Unfolding Saga of COVID-19. Front Immunol 2021; 12:724914. [PMID: 34745097 PMCID: PMC8564481 DOI: 10.3389/fimmu.2021.724914] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2021] [Accepted: 09/27/2021] [Indexed: 12/15/2022] Open
Abstract
The year 2019 has seen an emergence of the novel coronavirus named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causing coronavirus disease of 2019 (COVID-19). Since the onset of the pandemic, biological and interdisciplinary research is being carried out across the world at a rapid pace to beat the pandemic. There is an increased need to comprehensively understand various aspects of the virus from detection to treatment options including drugs and vaccines for effective global management of the disease. In this review, we summarize the salient findings pertaining to SARS-CoV-2 biology, including symptoms, hosts, epidemiology, SARS-CoV-2 genome, and its emerging variants, viral diagnostics, host-pathogen interactions, alternative antiviral strategies and application of machine learning heuristics and artificial intelligence for effective management of COVID-19 and future pandemics.
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Affiliation(s)
- Arvinpreet Kaur
- Department of Bioinformatics, Hans Raj Mahila Maha Vidyalaya, Punjab, India
- Bioclues.org, Hyderabad, India
| | - Mehak Chopra
- Centre for Bioinformatics, School of Life Sciences, Pondicherry University, Puducherry, India
| | - Mahak Bhushan
- Department of Biological Sciences, Indian Institute of Science Education and Research, Kolkata, India
| | - Sonal Gupta
- Bioclues.org, Hyderabad, India
- Department of Biotechnology and Bioinformatics, Birla Institute of Scientific Research, Jaipur, India
| | | | - Narmadhaa Sivagurunathan
- Department of Biotechnology and Bioinformatics, Birla Institute of Scientific Research, Jaipur, India
| | - Nidhi Shukla
- Bioclues.org, Hyderabad, India
- Department of Biotechnology and Bioinformatics, Birla Institute of Scientific Research, Jaipur, India
| | - Shalini Rajagopal
- Vignan’s Foundation for Science, Technology & Research (Deemed to be University), Guntur, India
| | - Purva Bhalothia
- Department of Biotechnology and Bioinformatics, Birla Institute of Scientific Research, Jaipur, India
| | - Purnima Sharma
- Department of Bioinformatics, Hans Raj Mahila Maha Vidyalaya, Punjab, India
| | - Jalaja Naravula
- Vignan’s Foundation for Science, Technology & Research (Deemed to be University), Guntur, India
| | - Renuka Suravajhala
- Bioclues.org, Hyderabad, India
- Department of Chemistry, School of Basic Sciences, Manipal University Jaipur, Jaipur, India
| | - Ayam Gupta
- Vignan’s Foundation for Science, Technology & Research (Deemed to be University), Guntur, India
| | - Bilal Ahmed Abbasi
- Functional Genomics Unit, Council of Scientific and Industrial Research- Institute of Genomics & Integrative Biology (CSIR-IGIB), Delhi, India
| | - Prittam Goswami
- Department of Biotechnology, Haldia Institute of Technology, West Bengal, India
| | - Harpreet Singh
- Department of Bioinformatics, Hans Raj Mahila Maha Vidyalaya, Punjab, India
- Bioclues.org, Hyderabad, India
| | - Rahul Narang
- Department of Microbiology, All India Institute of Medical Sciences, Bibinagar, Hyderabad, India
| | | | - Krishna Mohan Medicherla
- Department of Biotechnology and Bioinformatics, Birla Institute of Scientific Research, Jaipur, India
| | - Jayaraman Valadi
- Bioclues.org, Hyderabad, India
- Department of Computer Science, Flame University, Pune, India
| | - Anil Kumar S
- Vignan’s Foundation for Science, Technology & Research (Deemed to be University), Guntur, India
| | - Gyaneshwer Chaubey
- Cytogenetics Laboratory, Department of Zoology, Benaras Hindu University, Varanasi, India
| | - Keshav K. Singh
- Department of Genetics, University of Alabama, Birmingham, AL, United States
| | - Obul Reddy Bandapalli
- Bioclues.org, Hyderabad, India
- German Cancer Research Centre (DKFZ), Heidelberg, Germany
- Department of Applied Biology, Council of Scientific and Industrial Research-Indian Institute of Chemical Technology (CSIR-IICT), Hyderabad, India
| | - Polavarapu Bilhan Kavi Kishor
- Bioclues.org, Hyderabad, India
- Vignan’s Foundation for Science, Technology & Research (Deemed to be University), Guntur, India
| | - Prashanth Suravajhala
- Bioclues.org, Hyderabad, India
- Department of Biotechnology and Bioinformatics, Birla Institute of Scientific Research, Jaipur, India
- Amrita School of Biotechnology, Amrita Vishwa Vidyapeetham, Kerala, India
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Synergistic Block of SARS-CoV-2 Infection by Combined Drug Inhibition of the Host Entry Factors PIKfyve Kinase and TMPRSS2 Protease. J Virol 2021; 95:e0097521. [PMID: 34406858 PMCID: PMC8513479 DOI: 10.1128/jvi.00975-21] [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] [Indexed: 02/06/2023] Open
Abstract
Repurposing FDA-approved inhibitors able to prevent infection by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) could provide a rapid path to establish new therapeutic options to mitigate the effects of coronavirus disease 2019 (COVID-19). Proteolytic cleavages of the spike (S) protein of SARS-CoV-2, mediated by the host cell proteases cathepsin and TMPRSS2, alone or in combination, are key early activation steps required for efficient infection. The PIKfyve kinase inhibitor apilimod interferes with late endosomal viral traffic and through an ill-defined mechanism prevents in vitro infection through late endosomes mediated by cathepsin. Similarly, inhibition of TMPRSS2 protease activity by camostat mesylate or nafamostat mesylate prevents infection mediated by the TMPRSS2-dependent and cathepsin-independent pathway. Here, we combined the use of apilimod with camostat mesylate or nafamostat mesylate and found an unexpected ∼5- to 10-fold increase in their effectiveness to prevent SARS-CoV-2 infection in different cell types. Comparable synergism was observed using both a chimeric vesicular stomatitis virus (VSV) containing S of SARS-CoV-2 (VSV-SARS-CoV-2) and SARS-CoV-2. The substantial ∼5-fold or higher decrease of the half-maximal effective concentrations (EC50s) suggests a plausible treatment strategy based on the combined use of these inhibitors. IMPORTANCE Infection by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is causing the coronavirus disease 2019 (COVID-2019) global pandemic. There are ongoing efforts to uncover effective antiviral agents that could mitigate the severity of the disease by controlling the ensuing viral replication. Promising candidates include small molecules that inhibit the enzymatic activities of host proteins, thus preventing SARS-CoV-2 entry and infection. They include apilimod, an inhibitor of PIKfyve kinase, and camostat mesylate and nafamostat mesylate, inhibitors of TMPRSS2 protease. Our research is significant for having uncovered an unexpected synergism in the effective inhibitory activity of apilimod used together with camostat mesylate or nafamostat mesylate.
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27
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Cell Entry of Animal Coronaviruses. Viruses 2021; 13:v13101977. [PMID: 34696406 PMCID: PMC8540712 DOI: 10.3390/v13101977] [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: 09/10/2021] [Revised: 09/22/2021] [Accepted: 09/23/2021] [Indexed: 01/11/2023] Open
Abstract
Coronaviruses (CoVs) are a group of enveloped positive-sense RNA viruses and can cause deadly diseases in animals and humans. Cell entry is the first and essential step of successful virus infection and can be divided into two ongoing steps: cell binding and membrane fusion. Over the past two decades, stimulated by the global outbreak of SARS-CoV and pandemic of SARS-CoV-2, numerous efforts have been made in the CoV research. As a result, significant progress has been achieved in our understanding of the cell entry process. Here, we review the current knowledge of this essential process, including the viral and host components involved in cell binding and membrane fusion, molecular mechanisms of their interactions, and the sites of virus entry. We highlight the recent findings of host restriction factors that inhibit CoVs entry. This knowledge not only enhances our understanding of the cell entry process, pathogenesis, tissue tropism, host range, and interspecies-transmission of CoVs but also provides a theoretical basis to design effective preventive and therapeutic strategies to control CoVs infection.
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28
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Rahbar Saadat Y, Hosseiniyan Khatibi SM, Zununi Vahed S, Ardalan M. Host Serine Proteases: A Potential Targeted Therapy for COVID-19 and Influenza. Front Mol Biosci 2021; 8:725528. [PMID: 34527703 PMCID: PMC8435734 DOI: 10.3389/fmolb.2021.725528] [Citation(s) in RCA: 45] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2021] [Accepted: 08/11/2021] [Indexed: 12/23/2022] Open
Abstract
The ongoing pandemic illustrates limited therapeutic options for controlling SARS-CoV-2 infections, calling a need for additional therapeutic targets. The viral spike S glycoprotein binds to the human receptor angiotensin-converting enzyme 2 (ACE2) and then is activated by the host proteases. Based on the accessibility of the cellular proteases needed for SARS-S activation, SARS-CoV-2 entrance and activation can be mediated by endosomal (such as cathepsin L) and non-endosomal pathways. Evidence indicates that in the non-endosomal pathway, the viral S protein is cleaved by the furin enzyme in infected host cells. To help the virus enter efficiently, the S protein is further activated by the serine protease 2 (TMPRSS2), provided that the S has been cleaved by furin previously. In this review, important roles for host proteases within host cells will be outlined in SARS-CoV-2 infection and antiviral therapeutic strategies will be highlighted. Although there are at least five highly effective vaccines at this time, the appearance of the new viral mutations demands the development of therapeutic agents. Targeted inhibition of host proteases can be used as a therapeutic approach for viral infection.
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Kreutzberger AJ, Sanyal A, Ojha R, Pyle JD, Vapalahti O, Balistreri G, Kirchhausen T. Synergistic block of SARS-CoV-2 infection by combined drug inhibition of the host entry factors PIKfyve kinase and TMPRSS2 protease. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2021:2021.06.01.446623. [PMID: 34100014 PMCID: PMC8183009 DOI: 10.1101/2021.06.01.446623] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
Abstract
Repurposing FDA-approved inhibitors able to prevent infection by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) could provide a rapid path to establish new therapeutic options to mitigate the effects of coronavirus disease 2019 (COVID-19). Proteolytic cleavages of the spike S protein of SARS-CoV-2, mediated by the host cell proteases cathepsin and TMPRSS2, alone or in combination, are key early activation steps required for efficient infection. The PIKfyve kinase inhibitor apilimod interferes with late endosomal viral traffic, and through an ill-defined mechanism prevents in vitro infection through late endosomes mediated by cathepsin. Similarly, inhibition of TMPRSS2 protease activity by camostat mesylate or nafamostat mesylate prevents infection mediated by the TMPRSS2-dependent and cathepsin-independent pathway. Here, we combined the use of apilimod with camostat mesylate or nafamostat mesylate and found an unexpected ~5-10-fold increase in their effectiveness to prevent SARS-CoV-2 infection in different cell types. Comparable synergism was observed using both, a chimeric vesicular stomatitis virus (VSV) containing S of SARS-CoV-2 (VSV-SARS-CoV-2) and SARS-CoV-2 virus. The substantial ~5-fold or more decrease of half maximal effective concentrations (EC50 values) suggests a plausible treatment strategy based on the combined use of these inhibitors.
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Affiliation(s)
- Alex J.B. Kreutzberger
- Department of Cell Biology, Harvard Medical School, 200 Longwood Av, Boston, MA 02115, USA
- Program in Cellular and Molecular Medicine, Boston Children’s Hospital, 200 Longwood Av, Boston, MA 02115, USA
| | - Anwesha Sanyal
- Department of Cell Biology, Harvard Medical School, 200 Longwood Av, Boston, MA 02115, USA
- Program in Cellular and Molecular Medicine, Boston Children’s Hospital, 200 Longwood Av, Boston, MA 02115, USA
| | - Ravi Ojha
- Department of Virology, Faculty of Medicine, University of Helsinki, Helsinki, Finland
| | - Jesse D. Pyle
- Program in Virology, Harvard Medical School, 200 Longwood Ave, Boston, MA 02115, USA
| | - Olli Vapalahti
- Department of Virology, Faculty of Medicine, University of Helsinki, Helsinki, Finland
- Department of Veterinary Biosciences, University of Helsinki, Helsinki, Finland
- Virology and Immunology, Helsinki University Hospital Diagnostic Center (HUSLAB), Helsinki, Finland
| | - Giuseppe Balistreri
- Department of Virology, Faculty of Medicine, University of Helsinki, Helsinki, Finland
- Department of Veterinary Biosciences, University of Helsinki, Helsinki, Finland
| | - Tom Kirchhausen
- Department of Cell Biology, Harvard Medical School, 200 Longwood Av, Boston, MA 02115, USA
- Program in Cellular and Molecular Medicine, Boston Children’s Hospital, 200 Longwood Av, Boston, MA 02115, USA
- Department of Pediatrics, Harvard Medical School, 200 Longwood Ave, Boston, MA 02115, USA
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30
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Xiang Y, Wang M, Chen H, Chen L. Potential therapeutic approaches for the early entry of SARS-CoV-2 by interrupting the interaction between the spike protein on SARS-CoV-2 and angiotensin-converting enzyme 2 (ACE2). Biochem Pharmacol 2021; 192:114724. [PMID: 34371003 PMCID: PMC8349388 DOI: 10.1016/j.bcp.2021.114724] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2021] [Revised: 08/04/2021] [Accepted: 08/04/2021] [Indexed: 12/12/2022]
Abstract
The COVID-19 pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has quickly spread around the globe. At present, there is no precise and effective treatment for the patients with COVID-19, so rapid development of drugs is urgently needed in order to contain the highly infectious disease. The virus spike protein (S protein) can recognize the angiotensin-converting enzyme 2 (ACE2) receptor on the host cell membrane and undergo a series of conformational changes, protease cleavage and membrane fusion to complete the virus entry, so S protein is an important target for vaccine and drug development. Here we provide a brief overview of molecular mechanisms of virus entry, as well as some potential antiviral agents that act on S/ACE2 protein-protein interaction. Specifically, we focused on experimentally validated and/or computational prediction identified inhibitors that target SARS-CoV-2 S protein, ACE2 and enzymes associated with viral infection. This review offers valuable information for the discovery and development of potential antiviral agents in combating SARS-CoV-2. In addition, with the deepening understanding of the mechanism of SARS-CoV-2 infection, more targeted prevention and treatment drugs will be explored with the aid of the advanced technology in the future.
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Affiliation(s)
- Yusen Xiang
- Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Mengge Wang
- Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Hongzhuan Chen
- Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
| | - Lili Chen
- Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
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Bristogiannis S, Swan D, Thachil J. Thromboprophylaxis in COVID-19 - Rationale and considerations. Adv Biol Regul 2021; 81:100819. [PMID: 34332403 PMCID: PMC8299150 DOI: 10.1016/j.jbior.2021.100819] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2021] [Revised: 07/20/2021] [Accepted: 07/21/2021] [Indexed: 12/27/2022]
Abstract
The Corona Virus Disease-2019 (COVID-19) pandemic is associated with a very high incidence of thrombotic complications. The exact mechanisms for this excess risk for clots have not been elucidated although one of the often-quoted pathophysiological entity is immunothrombosis. Recognition of thrombotic complications early on in this pandemic led to an over-explosion of studies which looked at the benefits of anticoagulation to mitigate this risk. In this review, we examine the rationale for thromboprophylaxis in COVID-19 with particular reference to dosing and discuss what may guide the decision-making process to consider anticoagulation. In addition, we explore the rationale for thrombosis prevention measures in special populations including outpatient setting, pregnant females, children, those with high body mass index and those on extracorporeal membrane oxygenation.
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Affiliation(s)
- Sotirios Bristogiannis
- Department of Haematology, NHS Hillingdon Hospital, Pield Health Road, Uxbridge, United Kingdom.
| | - Dawn Swan
- Department of Haematology, University Hospital Galway, Galway, Ireland.
| | - Jecko Thachil
- Department of Haematology, Manchester University Hospitals, Oxford Road, Manchester, United Kingdom.
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Havranek B, Islam SM. An in silico approach for identification of novel inhibitors as potential therapeutics targeting COVID-19 main protease. J Biomol Struct Dyn 2021; 39:4304-4315. [PMID: 32544024 PMCID: PMC7309303 DOI: 10.1080/07391102.2020.1776158] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2020] [Accepted: 05/25/2020] [Indexed: 01/08/2023]
Abstract
Respiratory disease caused by a novel coronavirus, COVID-19, has been labeled a pandemic by the World Health Organization. Very little is known about the infection mechanism for this virus. More importantly, there are no drugs or vaccines that can cure or prevent a person from getting COVID-19. In this study, the binding affinity of 2692 protease inhibitor compounds that are known in the protein data bank, are calculated against the main protease of the novel coronavirus with docking and molecular dynamics (MD). Both the docking and MD methods predict the macrocyclic tissue factor-factor VIIa (PubChem ID: 118098670) inhibitor to bind strongly with the main protease with a binding affinity of -10.6 and -10.0 kcal/mol, respectively. The TF-FVIIa inhibitors are known to prevent the coagulation of blood and have antiviral activity as shown in the case of SARS coronavirus. Two more inhibitors, phenyltriazolinones (PubChem ID: 104161460) and allosteric HCV NS5B polymerase thumb pocket 2 (PubChem ID: 163632044) have shown antiviral activity and also have high affinity towards the main protease of COVID-19. Furthermore, these inhibitors interact with the catalytic dyad in the active site of the COVID-19 main protease that is especially important in viral replication. The calculated theoretical dissociation constants of the proposed COVID-19 inhibitors are found to be very similar to the experimental dissociation constant values of similar protease-inhibitor systems.Communicated by Ramaswamy H. Sarma.
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Affiliation(s)
- Brandon Havranek
- Department of Chemistry, University of Illinois at Chicago, Chicago, IL, USA
| | - Shahidul M. Islam
- Department of Chemistry, University of Illinois at Chicago, Chicago, IL, USA
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Sarker J, Das P, Sarker S, Roy AK, Momen AZMR. A Review on Expression, Pathological Roles, and Inhibition of TMPRSS2, the Serine Protease Responsible for SARS-CoV-2 Spike Protein Activation. SCIENTIFICA 2021; 2021:2706789. [PMID: 34336361 PMCID: PMC8313365 DOI: 10.1155/2021/2706789] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/22/2020] [Revised: 05/30/2021] [Accepted: 07/14/2021] [Indexed: 05/08/2023]
Abstract
SARS-CoV-2, the coronavirus responsible for the COVID-19 pandemic, uses the host cell membrane receptor angiotensin-converting enzyme 2 (ACE2) for anchoring its spike protein, and the subsequent membrane fusion process is facilitated by host membrane proteases. Recent studies have shown that transmembrane serine protease 2 (TMPRSS2), a protease known for similar role in previous coronavirus infections, severe acute respiratory syndrome (SARS), and Middle East respiratory syndrome (MERS), is responsible for the proteolytic cleavage of the SARS-CoV-2 spike protein, enabling host cell fusion of the virus. TMPRSS2 is known to be expressed in the epithelial cells of different sites including gastrointestinal, respiratory, and genitourinary system. The infection site of the SARS-CoV-2 correlates with the coexpression sites of ACE2 and TMPRSS2. Besides, age-, sex-, and comorbidity-associated variation in infection rate correlates with the expression rate of TMPRSS2 in those groups. These findings provide valid reasons for the assumption that inhibiting TMPRSS2 can have a beneficial effect in reducing the cellular entry of the virus, ultimately affecting the infection rate and case severity. Several drug development studies are going on to develop potential inhibitors of the protease, using both conventional and computational approaches. Complete understanding of the biological roles of TMPRSS2 is necessary before such therapies are applied.
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Affiliation(s)
- Jyotirmoy Sarker
- Department of Pharmacy, Jagannath University, Dhaka 1100, Bangladesh
- Department of Pharmacy Systems, Outcomes and Policy, University of Illinois at Chicago, Chicago, IL 60607, USA
| | - Pritha Das
- Independent Author, Dhaka 1207, Bangladesh
| | - Sabarni Sarker
- Department of Pharmacy, Jagannath University, Dhaka 1100, Bangladesh
| | - Apurba Kumar Roy
- Department of Genetic Engineering and Biotechnology, University of Rajshahi, Rajshahi 6205, Bangladesh
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S N N, B N R, C P, K S S, Ramakrishnappa T, B T K, S M J, M M, N A, Yallappa, D DP, T V R, E G, Bagoji M, Chandaragi SS. SARS-CoV 2 spike protein S1 subunit as an ideal target for stable vaccines: A bioinformatic study. MATERIALS TODAY. PROCEEDINGS 2021; 49:904-912. [PMID: 34307057 PMCID: PMC8279943 DOI: 10.1016/j.matpr.2021.07.163] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
The Covid-19 a pandemic infectious disease and affected life across the world resulting in over 188.65 million confirmed cases across 223 countries, territories and areas with 4.06 million deaths. It is caused by a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and spike (S) protein of SARS-CoV-2, which plays a key role in the receptor recognition and cell membrane fusion process, is composed of two subunits, S1 and S2. The S1 subunit contains a receptor-binding domain (RBD) that recognizes and binds to the host receptor angiotensin-converting enzyme 2 (ACE2), while the S2 subunit mediates viral cell membrane fusion. Hence, it is a key target for developing neutralizing antibodies. Here, we have performed phylogenetic analysis and structural modeling of the SARS-CoV-2 spike glycoprotein, which is found highly conserved. The overall percent protein sequence identity from the SARS-CoV-2 spike protein sequences from the NCBI database was 99.68%. The functional domains of the S protein reveal that the S1 subunit was highly conserved (99.70%) than the S2 subunit (99.66%). Further, the 319-541 residues (RBD) of amino acids within the S1 domain were 100% similar among the spike protein. The 3D modeling of SARS-CoV-2 spike glycoprotein indicated that S protein has four domains with five protein units and the S1 subunit from 1 to 289 amino acid of domain 1 is highly conserved without any change in the ligand interaction site. This analysis clearly suggests that the S1 subunit (RBD 319-541) can be used as a target region for stable and safe vaccine development.
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Affiliation(s)
- Nagesha S N
- Department of Biotechnology, College of Agriculture, Hassan, University of Agricultural Sciences, Bangalore 560065, Karnataka, India
| | - Ramesh B N
- Department of Biotechnology, College of Agriculture, Hassan, University of Agricultural Sciences, Bangalore 560065, Karnataka, India
| | - Pradeep C
- Department of Biotechnology, College of Agriculture, Hassan, University of Agricultural Sciences, Bangalore 560065, Karnataka, India
| | - Shashidhara K S
- Department of Genetics and Plant Breeding, College of Agriculture, Hassan, University of Agricultural Sciences, Bangalore 560065, Karnataka, India
| | - Thippeswamy Ramakrishnappa
- Department of Chemistry, BMS Institute of Technology and Management, Avalahalli, Yelahanka, Bengaluru 560064, Karnataka, India
| | - Krishnaprasad B T
- Department of Biotechnology, College of Agriculture, Hassan, University of Agricultural Sciences, Bangalore 560065, Karnataka, India
| | - Jnanashree S M
- Department of Biotechnology, College of Agriculture, Hassan, University of Agricultural Sciences, Bangalore 560065, Karnataka, India
| | - Manohar M
- Department of Biotechnology, College of Agriculture, Hassan, University of Agricultural Sciences, Bangalore 560065, Karnataka, India
| | - Arunkumar N
- Department of Biotechnology, College of Agriculture, Hassan, University of Agricultural Sciences, Bangalore 560065, Karnataka, India
| | - Yallappa
- Department of Biotechnology, College of Agriculture, Hassan, University of Agricultural Sciences, Bangalore 560065, Karnataka, India
| | - Dhanush Patel D
- Department of Biotechnology, College of Agriculture, Hassan, University of Agricultural Sciences, Bangalore 560065, Karnataka, India
| | - Rakesh T V
- Department of Biotechnology, College of Agriculture, Hassan, University of Agricultural Sciences, Bangalore 560065, Karnataka, India
| | - Girish E
- Department of Biotechnology, College of Agriculture, Hassan, University of Agricultural Sciences, Bangalore 560065, Karnataka, India
| | - Mahantesh Bagoji
- Department of Biotechnology, College of Agriculture, Hassan, University of Agricultural Sciences, Bangalore 560065, Karnataka, India
| | - Shreeram S Chandaragi
- Department of Biotechnology, College of Agriculture, Hassan, University of Agricultural Sciences, Bangalore 560065, Karnataka, India
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35
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Borges E, Setti AS, Iaconelli A, Braga DPDAF. Current status of the COVID-19 and male reproduction: A review of the literature. Andrology 2021; 9:1066-1075. [PMID: 33998143 PMCID: PMC8222884 DOI: 10.1111/andr.13037] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2020] [Revised: 04/09/2021] [Accepted: 05/11/2021] [Indexed: 12/26/2022]
Abstract
BACKGROUND Coronavirus disease 2019 (COVID-19), which causes serious respiratory illnesses such as pneumonia and lung failure, was first reported in mid-December 2019 in China and has spread around the world. In addition to causing serious respiratory illnesses such as pneumonia and lung failure, there have been conflicting reports about the presence of SARS-CoV-2 in the semen of patients who were previously diagnosed with COVID-19 and possible implications for the male reproductive tract. OBJECTIVE The goal for the present study was to review the current status of the literature concerning COVID-19 and male reproduction. MATERIAL AND METHODS An electronic literature search was done by using PubMed and Google Scholar databases. Relevant papers, concerning SARS-COV-2 and COVID-19 and male reproduction, published between January 2020 and December 2020 were selected, analyzed and eventually included in the present literature review. RESULTS SARS-CoV-2 may infect any cell type expressing angiotensin-converting enzyme 2 (ACE2), including reproductive cells. Besides the presence of the SARS-CoV-2 receptor, the expression of host proteases, such as transmembrane serine protease 2 (TMPRSS2), is needed to cleave the viral S protein, allowing permanent fusion of the viral and host cell membranes. Here, we aimed to review the current status of the literature concerning COVID-19 and male reproduction. The lack of co-expression of ACE2 and TMPRSS2 in the testis suggests that sperm cells may not be at increased risk of viral entry and spread. However, the presence of orchitis in COVID-19-confirmed patients and compromised sex-related hormonal balance among these patients intrigues reproductive medicine. DISCUSSION SARS-CoV-2 may use alternate receptors to enter certain cell types, or the expression of ACE2 and TMPRSS2 may not be detected in healthy individuals. CONCLUSION COVID-19 challenges all medical areas, including reproductive medicine. It is not yet clear what effects, if any, the COVID-19 pandemic will have on male reproduction. Further research is needed to understand the long-term impact of SARS-CoV-2 on male reproductive function.
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Affiliation(s)
- Edson Borges
- Fertility Medical GroupSão PauloBrazil
- Instituto Sapientiae – Centro de Estudos e Pesquisa em Reprodução Humana AssistidaSão PauloBrazil
| | - Amanda Souza Setti
- Fertility Medical GroupSão PauloBrazil
- Instituto Sapientiae – Centro de Estudos e Pesquisa em Reprodução Humana AssistidaSão PauloBrazil
| | - Assumpto Iaconelli
- Fertility Medical GroupSão PauloBrazil
- Instituto Sapientiae – Centro de Estudos e Pesquisa em Reprodução Humana AssistidaSão PauloBrazil
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Vianello A, Del Turco S, Babboni S, Silvestrini B, Ragusa R, Caselli C, Melani L, Fanucci L, Basta G. The Fight against COVID-19 on the Multi-Protease Front and Surroundings: Could an Early Therapeutic Approach with Repositioning Drugs Prevent the Disease Severity? Biomedicines 2021; 9:710. [PMID: 34201505 PMCID: PMC8301470 DOI: 10.3390/biomedicines9070710] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2021] [Revised: 06/17/2021] [Accepted: 06/17/2021] [Indexed: 12/15/2022] Open
Abstract
The interaction between the membrane spike (S) protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and the transmembrane angiotensin-converting enzyme 2 (ACE2) receptor of the human epithelial host cell is the first step of infection, which has a critical role for viral pathogenesis of the current coronavirus disease-2019 (COVID-19) pandemic. Following the binding between S1 subunit and ACE2 receptor, different serine proteases, including TMPRSS2 and furin, trigger and participate in the fusion of the viral envelope with the host cell membrane. On the basis of the high virulence and pathogenicity of SARS-CoV-2, other receptors have been found involved for viral binding and invasiveness of host cells. This review comprehensively discusses the mechanisms underlying the binding of SARS-CoV2 to ACE2 and putative alternative receptors, and the role of potential co-receptors and proteases in the early stages of SARS-CoV-2 infection. Given the short therapeutic time window within which to act to avoid the devastating evolution of the disease, we focused on potential therapeutic treatments-selected mainly among repurposing drugs-able to counteract the invasive front of proteases and mild inflammatory conditions, in order to prevent severe infection. Using existing approved drugs has the advantage of rapidly proceeding to clinical trials, low cost and, consequently, immediate and worldwide availability.
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Affiliation(s)
- Annamaria Vianello
- Department of Information Engineering, Telemedicine Section, University of Pisa, 56122 Pisa, Italy; (A.V.); (L.F.)
| | - Serena Del Turco
- Council of National Research (CNR), Institute of Clinical Physiology, 56124 Pisa, Italy; (S.B.); (R.R.); (C.C.)
| | - Serena Babboni
- Council of National Research (CNR), Institute of Clinical Physiology, 56124 Pisa, Italy; (S.B.); (R.R.); (C.C.)
| | - Beatrice Silvestrini
- Department of Surgical, Medical, Molecular Pathology, and Critical Area, University of Pisa, 56122 Pisa, Italy;
| | - Rosetta Ragusa
- Council of National Research (CNR), Institute of Clinical Physiology, 56124 Pisa, Italy; (S.B.); (R.R.); (C.C.)
| | - Chiara Caselli
- Council of National Research (CNR), Institute of Clinical Physiology, 56124 Pisa, Italy; (S.B.); (R.R.); (C.C.)
| | - Luca Melani
- Department of Territorial Medicine, ASL Toscana Nord-Ovest, 56121 Pisa, Italy;
| | - Luca Fanucci
- Department of Information Engineering, Telemedicine Section, University of Pisa, 56122 Pisa, Italy; (A.V.); (L.F.)
| | - Giuseppina Basta
- Council of National Research (CNR), Institute of Clinical Physiology, 56124 Pisa, Italy; (S.B.); (R.R.); (C.C.)
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Megyeri K, Dernovics Á, Al-Luhaibi ZII, Rosztóczy A. COVID-19-associated diarrhea. World J Gastroenterol 2021; 27:3208-3222. [PMID: 34163106 PMCID: PMC8218355 DOI: 10.3748/wjg.v27.i23.3208] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/28/2021] [Revised: 03/19/2021] [Accepted: 05/20/2021] [Indexed: 02/06/2023] Open
Abstract
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) recently emerged as a highly virulent respiratory pathogen that is known as the causative agent of coronavirus disease 2019 (COVID-19). Diarrhea is a common early symptom in a significant proportion of patients with SARS-CoV-2 infection. SARS-CoV-2 can infect and replicate in esophageal cells and enterocytes, leading to direct damage to the intestinal epithelium. The infection decreases the level of angiotensin-converting enzyme 2 receptors, thereby altering the composition of the gut microbiota. SARS-CoV-2 elicits a cytokine storm, which contributes to gastrointestinal inflammation. The direct cytopathic effects of SARS-CoV-2, gut dysbiosis, and aberrant immune response result in increased intestinal permeability, which may exacerbate existing symptoms and worsen the prognosis. By exploring the elements of pathogenesis, several therapeutic options have emerged for the treatment of COVID-19 patients, such as biologics and biotherapeutic agents. However, the presence of SARS-CoV-2 in the feces may facilitate the spread of COVID-19 through fecal-oral transmission and contaminate the environment. Thus gastrointestinal SARS-CoV-2 infection has important epidemiological significance. The development of new therapeutic and preventive options is necessary to treat and restrict the spread of this severe and widespread infection more effectively. Therefore, we summarize the key elements involved in the pathogenesis and the epidemiology of COVID-19-associated diarrhea.
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Affiliation(s)
- Klara Megyeri
- Department of Medical Microbiology and Immunobiology, University of Szeged, Szeged 6720, Csongrad, Hungary
| | - Áron Dernovics
- Department of Medical Microbiology and Immunobiology, University of Szeged, Szeged 6720, Csongrad, Hungary
| | - Zaid I I Al-Luhaibi
- Department of Medical Microbiology and Immunobiology, University of Szeged, Szeged 6720, Csongrad, Hungary
| | - András Rosztóczy
- Division of Gastroenterology, Department of Internal Medicine, University of Szeged, Szeged 6720, Csongrad, Hungary
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Alam S, Kamal TB, Sarker MMR, Zhou JR, Rahman SMA, Mohamed IN. Therapeutic Effectiveness and Safety of Repurposing Drugs for the Treatment of COVID-19: Position Standing in 2021. Front Pharmacol 2021; 12:659577. [PMID: 34220503 PMCID: PMC8243370 DOI: 10.3389/fphar.2021.659577] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2021] [Accepted: 04/28/2021] [Indexed: 02/06/2023] Open
Abstract
COVID-19, transmitted by SARS-CoV-2, is one of the most serious pandemic situations in the history of mankind, and has already infected a huge population across the globe. This horrendously contagious viral outbreak was first identified in China and within a very short time it affected the world's health, transport, economic, and academic sectors. Despite the recent approval of a few anti-COVID-19 vaccines, their unavailability and insufficiency along with the lack of other potential therapeutic options are continuing to worsen the situation, with valuable lives continuing to be lost. In this situation, researchers across the globe are focusing on repurposing prospective drugs and prophylaxis such as favipiravir, remdesivir, chloroquine, hydroxychloroquine, ivermectin, lopinavir-ritonavir, azithromycin, doxycycline, ACEIs/ARBs, rivaroxaban, and protease inhibitors, which were preliminarily based on in vitro and in vivo pharmacological and toxicological study reports followed by clinical applications. Based on available preliminary data derived from limited clinical trials, the US National Institute of Health (NIH) and USFDA also recommended a few drugs to be repurposed i.e., hydroxychloroquine, remdesivir, and favipiravir. However, World Health Organization later recommended against the use of chloroquine, hydroxychloroquine, remdesivir, and lopinavir/ritonavir in the treatment of COVID-19 infections. Combining basic knowledge of viral pathogenesis and pharmacodynamics of drug molecules as well as in silico approaches, many drug candidates have been investigated in clinical trials, some of which have been proven to be partially effective against COVID-19, and many of the other drugs are currently under extensive screening. The repurposing of prospective drug candidates from different stages of evaluation can be a handy wellspring in COVID-19 management and treatment along with approved anti-COVID-19 vaccines. This review article combined the information from completed clinical trials, case series, cohort studies, meta-analyses, and retrospective studies to focus on the current status of repurposing drugs in 2021.
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Affiliation(s)
- Safaet Alam
- Department of Pharmacy, State University of Bangladesh, Dhaka, Bangladesh
| | | | - Md. Moklesur Rahman Sarker
- Department of Pharmacy, State University of Bangladesh, Dhaka, Bangladesh
- Pharmacology and Toxicology Research Division, Health Med Science Research Limited, Dhaka, Bangladesh
| | - Jin-Rong Zhou
- Nutrition/Metabolism Laboratory, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, United States
| | - S. M. Abdur Rahman
- Department of Clinical Pharmacy and Pharmacology, Faculty of Pharmacy, University of Dhaka, Dhaka, Bangladesh
| | - Isa Naina Mohamed
- Pharmacology Department, Medical Faculty, Universiti Kebangsaan Malaysia (The National University of Malaysia), Kuala Lumpur, Malaysia
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Souza PFN, Mesquita FP, Amaral JL, Landim PGC, Lima KRP, Costa MB, Farias IR, Lima LB, Montenegro RC. The human pandemic coronaviruses on the show: The spike glycoprotein as the main actor in the coronaviruses play. Int J Biol Macromol 2021; 179:1-19. [PMID: 33667553 PMCID: PMC7921731 DOI: 10.1016/j.ijbiomac.2021.02.203] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2021] [Revised: 02/25/2021] [Accepted: 02/26/2021] [Indexed: 01/28/2023]
Abstract
Three coronaviruses (CoVs) have threatened the world population by causing outbreaks in the last two decades. In late 2019, the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) emerged and caused the coronaviruses to disease 2019 (COVID-19), leading to the ongoing global outbreak. The other pandemic coronaviruses, SARS-CoV and Middle East respiratory syndrome CoV (MERS-CoV), share a considerable level of similarities at genomic and protein levels. However, the differences between them lead to distinct behaviors. These differences result from the accumulation of mutations in the sequence and structure of spike (S) glycoprotein, which plays an essential role in coronavirus infection, pathogenicity, transmission, and evolution. In this review, we brought together many studies narrating a sequence of events and highlighting the differences among S proteins from SARS-CoV, MERS-CoV, and SARS-CoV-2. It was performed here, analysis of S protein sequences and structures from the three pandemic coronaviruses pointing out the mutations among them and what they come through. Additionally, we investigated the receptor-binding domain (RBD) from all S proteins explaining the mutation and biological importance of all of them. Finally, we discuss the mutation in the S protein from several new isolates of SARS-CoV-2, reporting their difference and importance. This review brings into detail how the variations in S protein that make SARS-CoV-2 more aggressive than its relatives coronaviruses and other differences between coronaviruses.
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Affiliation(s)
- Pedro F N Souza
- Department of Biochemistry and Molecular Biology, Federal University of Ceara, Brazil.
| | - Felipe P Mesquita
- Drug research and Development Center, Department of Medicine, Federal University of Ceara, Brazil
| | - Jackson L Amaral
- Department of Biochemistry and Molecular Biology, Federal University of Ceara, Brazil
| | - Patrícia G C Landim
- Department of Biochemistry and Molecular Biology, Federal University of Ceara, Brazil
| | - Karollyny R P Lima
- Department of Biochemistry and Molecular Biology, Federal University of Ceara, Brazil
| | - Marília B Costa
- Drug research and Development Center, Department of Medicine, Federal University of Ceara, Brazil
| | - Izabelle R Farias
- Drug research and Development Center, Department of Medicine, Federal University of Ceara, Brazil
| | - Luina B Lima
- Drug research and Development Center, Department of Medicine, Federal University of Ceara, Brazil
| | - Raquel C Montenegro
- Drug research and Development Center, Department of Medicine, Federal University of Ceara, Brazil
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Ageno W, De Candia E, Iacoviello L, Di Castelnuovo A. Protective effect of oral anticoagulant drugs in atrial fibrillation patients admitted for COVID-19: Results from the CORIST study. Thromb Res 2021; 203:138-141. [PMID: 34020162 PMCID: PMC8123369 DOI: 10.1016/j.thromres.2021.05.006] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2021] [Revised: 04/19/2021] [Accepted: 05/10/2021] [Indexed: 01/25/2023]
Affiliation(s)
- Walter Ageno
- Department of Medicine and Surgery, University of Insubria, Varese, Italy.
| | - Erica De Candia
- Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Università Cattolica del Sacro Cuore, Roma, Italy
| | - Licia Iacoviello
- Department of Medicine and Surgery, University of Insubria, Varese, Italy; Department of Epidemiology and Prevention, IRCCS Neuromed, Pozzilli, IS, Italy
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Suganya S, Divya S, Parani M. Severe acute respiratory syndrome-coronavirus-2: Current advances in therapeutic targets and drug development. Rev Med Virol 2021; 31:e2174. [PMID: 32965078 PMCID: PMC7537282 DOI: 10.1002/rmv.2174] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2020] [Revised: 09/05/2020] [Accepted: 09/08/2020] [Indexed: 12/23/2022]
Abstract
The current pandemic of severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) has quickly emerged as a global health concern with government bodies worldwide taking drastic control measures. Understanding the virology of SARS-CoV-2, its molecular mechanisms, and its pathogenesis are required for a targeted therapeutic approach. In this review, we highlight the current molecular and drug advances that target SARS-CoV-2 at the genome level. We also summarize studies that therapeutically target the host angiotensin-converting enzyme 2 and proteases. Finally, we summarize antibody-mediated therapeutic approaches, as well as recent trends in vaccine development. Hence, the purpose of this study is to investigate different molecular targets in SARS-CoV-2 pathogenesis and their usefulness in developing strategies for drug development.
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Affiliation(s)
- Sakthivel Suganya
- Department of PsychologyTMC AcademySingapore
- Genome Research CenterAcademia SinicaTaipei CityTaiwan, ROC
| | - Suresh Divya
- Department of PediatricsNational Taiwan University HospitalYunlin CountyTaiwan, ROC
- Department of Genetic EngineeringGenomics LaboratorySRM Institute of Science and TechnologyKattankulathurTamil NaduIndia
| | - Madasamy Parani
- Department of Genetic EngineeringGenomics LaboratorySRM Institute of Science and TechnologyKattankulathurTamil NaduIndia
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Oz M, Lorke DE, Kabbani N. A comprehensive guide to the pharmacologic regulation of angiotensin converting enzyme 2 (ACE2), the SARS-CoV-2 entry receptor. Pharmacol Ther 2021; 221:107750. [PMID: 33275999 PMCID: PMC7854082 DOI: 10.1016/j.pharmthera.2020.107750] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2020] [Revised: 11/18/2020] [Accepted: 11/19/2020] [Indexed: 02/06/2023]
Abstract
The recent emergence of coronavirus disease-2019 (COVID-19) as a global pandemic has prompted scientists to address an urgent need for defining mechanisms of disease pathology and treatment. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent for COVID-19, employs angiotensin converting enzyme 2 (ACE2) as its primary target for cell surface attachment and likely entry into the host cell. Thus, understanding factors that may regulate the expression and function of ACE2 in the healthy and diseased body is critical for clinical intervention. Over 66% of all adults in the United States are currently using a prescription drug and while earlier findings have focused on possible upregulation of ACE2 expression through the use of renin angiotensin system (RAS) inhibitors, mounting evidence suggests that various other widely administered drugs used in the treatment of hypertension, heart failure, diabetes mellitus, hyperlipidemias, coagulation disorders, and pulmonary disease may also present a varied risk for COVID-19. Specifically, we summarize mechanisms on how heparin, statins, steroids and phytochemicals, besides their established therapeutic effects, may also interfere with SARS-CoV-2 viral entry into cells. We also describe evidence on the effect of several vitamins, phytochemicals, and naturally occurring compounds on ACE2 expression and activity in various tissues and disease models. This comprehensive review aims to provide a timely compendium on the potential impact of commonly prescribed drugs and pharmacologically active compounds on COVID-19 pathology and risk through regulation of ACE2 and RAS signaling.
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Key Words
- adam17, a disintegrin and metalloprotease 17
- ace, angiotensin i converting enzyme
- ace-inh., angiotensin i converting enzyme inhibitor
- ampk, amp-activated protein kinase
- ang-ii, angiotensin ii
- arb, angiotensin ii type 1-receptor blocker
- ards, acute respiratory distress syndrome
- at1-r, angiotensin ii type 1-receptor
- βarb, β-adrenergic receptor blockers
- bk, bradykinin
- ccb, calcium channel blockers
- ch25h, cholesterol-25-hydroxylase
- copd, chronic obstructive lung disease
- cox, cyclooxygenase
- covid-19, coronavirus disease-2019
- dabk, [des-arg9]-bradykinin
- erk, extracellular signal-regulated kinase
- 25hc, 25-hydroxycholesterol
- hs, heparan sulfate
- hspg, heparan sulfate proteoglycan
- ibd, inflammatory bowel disease
- map, mitogen-activated protein
- mers, middle east respiratory syndrome
- mrb, mineralocorticoid receptor blocker
- nos, nitric oxide synthase
- nsaid, non-steroid anti-inflammatory drug
- ras, renin-angiotensin system
- sars-cov, severe acute respiratory syndrome coronavirus
- sh, spontaneously hypertensive
- s protein, spike protein
- sirt1, sirtuin 1
- t2dm, type 2 diabetes mellitus
- tcm, traditional chinese medicine
- tmprss2, transmembrane protease, serine 2
- tnf, tumor necrosis factor
- ufh, unfractionated heparin
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Affiliation(s)
- Murat Oz
- Department of Pharmacology and Therapeutics, Faculty of Pharmacy, Kuwait University, Safat 13110, Kuwait.
| | - Dietrich Ernst Lorke
- Department of Anatomy and Cellular Biology, College of Medicine and Health Sciences, Khalifa University, Abu Dhabi, United Arab Emirates; Center for Biotechnology, Khalifa University of Science and Technology, Abu Dhabi, United Arab Emirates
| | - Nadine Kabbani
- School of Systems Biology, George Mason University, Fairfax, VA 22030, USA
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Savla SR, Prabhavalkar KS, Bhatt LK. Cytokine storm associated coagulation complications in COVID-19 patients: Pathogenesis and Management. Expert Rev Anti Infect Ther 2021; 19:1397-1413. [PMID: 33832398 PMCID: PMC8074652 DOI: 10.1080/14787210.2021.1915129] [Citation(s) in RCA: 51] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Introduction SARS-CoV-2, the causative agent of COVID-19, attacks the immune system causing an exaggerated and uncontrolled release of pro-inflammatory mediators (cytokine storm). Recent studies propose an active role of coagulation disorders in disease progression. This hypercoagulability has been displayed by marked increase in D-dimer in hospitalized patients. Areas Covered This review summarizes the pathogenesis of SARS-CoV-2 infection, generation of cytokine storm, the interdependence between inflammation and coagulation, its consequences and the possible management options for coagulation complications like venous thromboembolism (VTE), microthrombosis, disseminated intravascular coagulation (DIC), and systemic and local coagulopathy. We searched PubMed, Scopus, and Google Scholar for relevant reports using COVID-19, cytokine storm, and coagulation as keywords. Expert Opinion A prophylactic dose of 5000–7500 units of low molecular weight heparin (LMWH) has been recommended for hospitalized COVID-19 patients in order to prevent VTE. Treatment dose of LMWH, based on disease severity, is being contemplated for patients showing a marked rise in levels of D-dimer due to possible pulmonary thrombi. Additionally, targeting PAR-1, thrombin, coagulation factor Xa and the complement system may be potentially useful in reducing SARS-CoV-2 infection induced lung injury, microvascular thrombosis, VTE and related outcomes like DIC and multi-organ failure.
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Affiliation(s)
- Shreya R Savla
- Department of Pharmacology, Dr. Bhanuben Nanavati College of Pharmacy, Vile Parle (West), Mumbai, 400056, India
| | - Kedar S Prabhavalkar
- Department of Pharmacology, Dr. Bhanuben Nanavati College of Pharmacy, Vile Parle (West), Mumbai, 400056, India
| | - Lokesh K Bhatt
- Department of Pharmacology, Dr. Bhanuben Nanavati College of Pharmacy, Vile Parle (West), Mumbai, 400056, India
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Böhm R, Bulin C, Waetzig V, Cascorbi I, Klein HJ, Herdegen T. Pharmacovigilance-based drug repurposing: The search for inverse signals via OpenVigil identifies putative drugs against viral respiratory infections. Br J Clin Pharmacol 2021; 87:4421-4431. [PMID: 33871897 DOI: 10.1111/bcp.14868] [Citation(s) in RCA: 61] [Impact Index Per Article: 15.3] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2020] [Revised: 03/25/2021] [Accepted: 04/06/2021] [Indexed: 12/19/2022] Open
Affiliation(s)
- Ruwen Böhm
- Institute of Experimental and Clinical Pharmacology, University Hospital Schleswig-Holstein Campus Kiel, Germany
| | - Claudia Bulin
- Institute of Experimental and Clinical Pharmacology, University Hospital Schleswig-Holstein Campus Kiel, Germany
| | - Vicki Waetzig
- Institute of Experimental and Clinical Pharmacology, University Hospital Schleswig-Holstein Campus Kiel, Germany
| | - Ingolf Cascorbi
- Institute of Experimental and Clinical Pharmacology, University Hospital Schleswig-Holstein Campus Kiel, Germany
| | | | - Thomas Herdegen
- Institute of Experimental and Clinical Pharmacology, University Hospital Schleswig-Holstein Campus Kiel, Germany
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Kastenhuber ER, Jaimes JA, Johnson JL, Mercadante M, Muecksch F, Weisblum Y, Bram Y, Schwartz RE, Whittaker GR, Cantley LC. Coagulation factors directly cleave SARS-CoV-2 spike and enhance viral entry. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2021. [PMID: 33821268 DOI: 10.1101/2021.03.31.437960] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Coagulopathy is recognized as a significant aspect of morbidity in COVID-19 patients. The clotting cascade is propagated by a series of proteases, including factor Xa and thrombin. Other host proteases, including TMPRSS2, are recognized to be important for cleavage activation of SARS-CoV-2 spike to promote viral entry. Using biochemical and cell-based assays, we demonstrate that factor Xa and thrombin can also directly cleave SARS-CoV-2 spike, enhancing viral entry. A drug-repurposing screen identified a subset of protease inhibitors that promiscuously inhibited spike cleavage by both transmembrane serine proteases as well as coagulation factors. The mechanism of the protease inhibitors nafamostat and camostat extend beyond inhibition of TMPRSS2 to coagulation-induced spike cleavage. Anticoagulation is critical in the management of COVID-19, and early intervention could provide collateral benefit by suppressing SARS-CoV-2 viral entry. We propose a model of positive feedback whereby infection-induced hypercoagulation exacerbates SARS-CoV-2 infectivity.
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How the Heart Was Involved in COVID-19 during the First Pandemic Phase: A Review. EPIDEMIOLGIA (BASEL, SWITZERLAND) 2021; 2:124-139. [PMID: 36417195 PMCID: PMC9620895 DOI: 10.3390/epidemiologia2010011] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/24/2020] [Revised: 02/10/2021] [Accepted: 03/12/2021] [Indexed: 12/15/2022]
Abstract
Coronavirus disease (COVID-19) was first observed in Wuhan, Hubei Province (China) in December 2019, resulting in an acute respiratory syndrome. Only later was COVID-19 considered a public health emergency of international concern and, on 11 March 2020, the WHO classified it as pandemic. Despite being a respiratory virus, the clinical manifestations are also characterized by cardiological involvement, especially in patients suffering from previous comorbidities such as hypertension and diabetes mellitus, its complications being potentially serious or fatal. Despite the efforts made by the scientific community to identify pathophysiological mechanisms, they still remain unclear. A fundamental role is played by the angiotensin 2 converting enzyme, known for its effects at the cardiovascular level and for its involvement in COVID-19 pathogenesis. The goal of this paper was to highlight the mechanisms and knowledge related to cardiovascular involvement during the first pandemic phase, as well as to emphasize the main cardiological complications in infected patients.
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47
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Kaur U, Chakrabarti SS, Ojha B, Pathak BK, Singh A, Saso L, Chakrabarti S. Targeting Host Cell Proteases to Prevent SARS-CoV-2 Invasion. Curr Drug Targets 2021; 22:192-201. [PMID: 32972339 DOI: 10.2174/1389450121666200924113243] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2020] [Revised: 08/16/2020] [Accepted: 08/26/2020] [Indexed: 11/22/2022]
Abstract
Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has spread worldwide and caused widespread devastation. In the absence of definitive therapy, symptomatic management remains the standard of care. Repurposing of many existing drugs, including several anti-viral drugs, is being attempted to tackle the COVID-19 pandemic. However, most of them have failed to show significant benefit in clinical trials. An attractive approach may be to target host proteases involved in SARS-CoV-2 pathogenesis. The priming of the spike (S) protein of the virus by proteolytic cleavage by the transmembrane serine protease-2 (TMPRSS2) is necessary for the fusion of the virus to the host cell after it binds to its receptor angiotensin converting enzyme-2 (ACE2). There are other proteases with varying spatiotemporal locations that may be important for viral entry and subsequent replication inside the cells, and these include trypsin, furin and cathepsins. In this report, we have discussed the tentative therapeutic role of inhibitors of TMPRSS2, cathepsin, trypsin, furin, plasmin, factor X and elastase in infection caused by SARS-CoV-2. Both available evidence, as well as hypotheses, are discussed, with emphasis on drugs which are approved for other indications such as bromhexine, ammonium chloride, nafamostat, camostat, tranexamic acid, epsilon amino-caproic acid, chloroquine, ulinastatin, aprotinin and anticoagulant drugs. Simultaneously, novel compounds being tested and problems with using these agents are also discussed.
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Affiliation(s)
- Upinder Kaur
- Department of Pharmacology, Institute of Medical Sciences, Banaras Hindu University, Varanasi, UP, India
| | - Sankha Shubhra Chakrabarti
- Department of Geriatric Medicine, Institute of Medical Sciences, Banaras Hindu University, Varanasi, UP, India
| | - Bisweswar Ojha
- Department of Physiology and Pharmacology, Sapienza University of Rome, Rome, India
| | - Bhairav Kumar Pathak
- Department of Biochemistry and Central Research Cell, MM Institute of Medical Sciences and Research, Maharishi Markandeshwar (deemed to be) University, Mullana, Ambala, Haryana, India
| | - Amit Singh
- Department of Physiology and Pharmacology, Sapienza University of Rome, Rome, India
| | - Luciano Saso
- Department of Physiology and Pharmacology, Sapienza University of Rome, Rome, Italy
| | - Sasanka Chakrabarti
- Department of Physiology and Pharmacology, Sapienza University of Rome, Rome, India
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49
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Abstract
Lymphopenia is commonly observed in SARS and COVID-19 patients although the lymphocyte count is not always below 0.8 × 109 /L in all the patients. It is suggested that lymphopenia serves as a useful predictor for prognosis in the patients. It is also hypothesized that lymphopenia is related to glucocorticoids and apoptosis. However, the ordering between lymphopenia and apoptosis appears different between SARS and COVID-19 patients, ie, lymphopenia is prior to apoptosis in SARS patients whereas apoptosis is prior to lymphopenia in COVID-19 patients. This paper attempts to figure out this contradiction through three players, lymphopenia, glucocorticoids, and apoptosis. Although the literature does not provide a solid explanation, the level of glucocorticoids could determine the ordering between lymphopenia and apoptosis because the administration of high doses of glucocorticoids could lead to lymphopenia whereas low doses of glucocorticoids could benefit patients. In the meantime, this paper raises several questions, which need to be answered in order to better understand the whole course of COVID-19.
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Affiliation(s)
- Shaomin Yan
- National Engineering Research Center for Non‐Food BiorefineryState Key Laboratory of Non‐Food Biomass and Enzyme TechnologyGuangxi Biomass Engineering Technology Research CenterGuangxi Key Laboratory of BiorefineryGuangxi Academy of SciencesNanningGuangxiChina
| | - Guang Wu
- National Engineering Research Center for Non‐Food BiorefineryState Key Laboratory of Non‐Food Biomass and Enzyme TechnologyGuangxi Biomass Engineering Technology Research CenterGuangxi Key Laboratory of BiorefineryGuangxi Academy of SciencesNanningGuangxiChina
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50
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Godino C, Scotti A, Maugeri N, Mancini N, Fominskiy E, Margonato A, Landoni G. Antithrombotic therapy in patients with COVID-19? -Rationale and Evidence. Int J Cardiol 2021; 324:261-266. [PMID: 33002521 PMCID: PMC7521414 DOI: 10.1016/j.ijcard.2020.09.064] [Citation(s) in RCA: 47] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/11/2020] [Revised: 09/09/2020] [Accepted: 09/24/2020] [Indexed: 12/30/2022]
Abstract
In patients with severe or critical Coronavirus disease 2019 (COVID-19) manifestations, a thromboinflammatory syndrome, with diffuse microvascular thrombosis, is increasingly evident as the final step of pro-inflammatory cytokines storm. Actually, no proven effective therapies for novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection exist. Preliminary observations on anticoagulant therapy appear to be associated with better outcomes in moderate and severe COVID-19 patients with signs of coagulopathy and in those requiring mechanical ventilation. The pathophysiology underlying the prothrombotic state elicited by SARS-CoV-2 outlines possible protective mechanisms of antithrombotic therapy (in primis anticoagulants) for this viral illness. The indications for antiplatelet/anticoagulant use (prevention, prophylaxis, therapy) are guided by the clinical context and the COVID-19 severity. We provide a practical approach on antithrombotic therapy management for COVID-19 patients from a multidisciplinary point of view.
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Affiliation(s)
- Cosmo Godino
- Clinical Cardiology Unit, Faculty of Medicine, IRCCS San Raffaele Scientific Institute, Milan, Italy.
| | - Andrea Scotti
- Department of Cardiac, Thoracic, Vascular Sciences and Public Health, University of Padua Medical School, Padua, Italy
| | - Norma Maugeri
- Division of Immunology, Transplantation and Infectious Diseases, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Nicasio Mancini
- Laboratory of Medical Microbiology and Virology, IRCCS San Raffaele Scientific Institute, Milan, Italy; Faculty of Medicine, Vita Salute San Raffaele University, Milan, Italy
| | - Evgeny Fominskiy
- Department of Anesthesia and Intensive Care, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Alberto Margonato
- Clinical Cardiology Unit, Faculty of Medicine, IRCCS San Raffaele Scientific Institute, Milan, Italy; Faculty of Medicine, Vita Salute San Raffaele University, Milan, Italy
| | - Giovanni Landoni
- Department of Anesthesia and Intensive Care, IRCCS San Raffaele Scientific Institute, Milan, Italy; Faculty of Medicine, Vita Salute San Raffaele University, Milan, Italy
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