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Abedi Dorcheh F, Balmeh N, Hejazi SH, Allahyari Fard N. Investigation of the mutated antimicrobial peptides to inhibit ACE2, TMPRSS2 and GRP78 receptors of SARS-CoV-2 and angiotensin II type 1 receptor (AT1R) as well as controlling COVID-19 disease. J Biomol Struct Dyn 2025; 43:1641-1664. [PMID: 38109185 DOI: 10.1080/07391102.2023.2292307] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2022] [Accepted: 11/23/2023] [Indexed: 12/19/2023]
Abstract
SARS-CoV-2 is a global problem nowadays. Based on studies, some human receptors are involved in binding to SARS-CoV-2. Thus, the inhibition of these receptors can be effective in the treatment of Covid-19. Because of the proven benefits of antimicrobial peptides (AMPs) and the side effects of chemical drugs, they can be known as an alternative to recent medicines. RCSB PDB to obtain PDB id, StraPep and PhytAMP to acquire Bio-AMPs information and 3-D structure, and AlgPred, Toxinpred, TargetAntiAngio, IL-4pred, IL-6pred, ACPred and Hemopred databases were used to find the best score peptide features. HADDOCK 2.2 was used for molecular docking analysis, and UCSF Chimera software version 1.15, SWISS-MODEL and BIOVIA Discovery Studio Visualizer4.5 were used for mutation and structure modeling. Furthermore, MD simulation results were achieved from GROMACS 4.6.5. Based on the obtained results, the Moricin peptide was found to have the best affinity for ACE2. Moreover, Bacteriocin leucocin-A had the highest affinity for GRP78, Cathelicidin-6 had the best affinity for AT1R, and Bacteriocin PlnK had the best binding affinity for TMPRSS2. Additionally, Bacteriocin glycocin F, Bacteriocin lactococcin-G subunit beta and Cathelicidin-6 peptides were the most common compounds among the four receptors. However, these peptides also have some side effects. Consequently, the mutation eliminated the side effects, and MD simulation results indicated that the mutation proved the result of the docking analysis. The effect of AMPs on ACE2, GRP78, TMPRSS2 and AT1R receptors can be a novel treatment for Covid-19.Communicated by Ramaswamy H. Sarma.
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Affiliation(s)
- Fatemeh Abedi Dorcheh
- Department of Biotechnology, School of Bioscience and Biotechnology, Shahid Ashrafi Esfahani University of Isfahan, Sepahan Shahr, Iran
| | - Negar Balmeh
- Skin Diseases and Leishmaniasis Research Center, Department of Parasitology and Mycology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Seyed Hossein Hejazi
- Skin Diseases and Leishmaniasis Research Center, Department of Parasitology and Mycology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Najaf Allahyari Fard
- Department of Systems Biotechnology, National Institute of Genetic Engineering & Biotechnology (NIGEB), Tehran, Iran
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Tian L, Wang Q, Zhou Z, Liu X, Zhang M, Yan G. Predicting drug combination side effects based on a metapath-based heterogeneous graph neural network. BMC Bioinformatics 2025; 26:16. [PMID: 39815175 PMCID: PMC11734363 DOI: 10.1186/s12859-024-06028-6] [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: 06/24/2024] [Accepted: 12/27/2024] [Indexed: 01/18/2025] Open
Abstract
In recent years, combined drug screening has played a very important role in modern drug discovery. Generally, synergistic drug combinations are crucial in treatment for many diseases. However, the toxic side effects of drug combinations are probably increased with the increase of drugs numbers, so the accurate prediction of toxic side effects of drug combinations is equally important. In this paper, we built a Metapath-based Aggregated Embedding Model on Single Drug-Side Effect Heterogeneous Information Network (MAEM-SSHIN), which extracts feature from a heterogeneous information network of single drug side effects, and a Graph Convolutional Network on Combinatorial drugs and Side effect Heterogeneous Information Network (GCN-CSHIN), which transforms the complex task of predicting multiple side effects between drug pairs into the more manageable prediction of relationships between combinatorial drugs and individual side effects. MAEM-SSHIN and GCN-CSHIN provided a united novel framework for predicting potential side effects in combinatorial drug therapies. This integration enhances prediction accuracy, efficiency, and scalability. Our experimental results demonstrate that this combined framework outperforms existing methodologies in predicting side effects, and marks a significant advancement in pharmaceutical research.
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Affiliation(s)
- Leixia Tian
- Beijing School, Beijing, 100088, China
- Academy of Mathematics and Systems Science, Chinese Academy of Sciences, Beijing, 100190, China
- University of Chinese Academy of Sciences, Beijing, 100190, China
| | - Qi Wang
- College of Science, China Agricultural University, Beijing, 100083, China
| | - Zhiheng Zhou
- Academy of Mathematics and Systems Science, Chinese Academy of Sciences, Beijing, 100190, China
- University of Chinese Academy of Sciences, Beijing, 100190, China
| | - Xiya Liu
- Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China
| | - Ming Zhang
- Academy of Mathematics and Systems Science, Chinese Academy of Sciences, Beijing, 100190, China
- University of Chinese Academy of Sciences, Beijing, 100190, China
| | - Guiying Yan
- Academy of Mathematics and Systems Science, Chinese Academy of Sciences, Beijing, 100190, China.
- University of Chinese Academy of Sciences, Beijing, 100190, China.
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Raouf GA, Mohammad FK, Merza MA. Polypharmacy and the In Silico Prediction of Potential Body Proteins Targeted by These Drugs Among Hospitalized COVID-19 Patients With Cytokine Storm. Cureus 2023; 15:e48834. [PMID: 38106718 PMCID: PMC10722521 DOI: 10.7759/cureus.48834] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/15/2023] [Indexed: 12/19/2023] Open
Abstract
Background and objective Polypharmacy is prevalent in coronavirus disease 2019 (COVID-19) patients with severe disease. However, information on polypharmacy among COVID-19 patients who also suffer from cytokine storm is scarce. In light of this, the purpose of the present study was to assess the incidence of polypharmacy and in silico prediction of potential body proteins targeted by these drugs among hospitalized COVID-19 patients who were identified to have the additional burden of cytokine storm in the city of Duhok, Kurdistan Region, Iraq. Methods This was a cross-sectional observational study conducted from June 2021 to April 2022; the phenomena of major polypharmacy (six to nine medications) and excessive polypharmacy (≥10 medications) were documented among 33 (15 males and 18 females) COVID-19 patients with cytokine storm during their hospital stay (8-45 days) in Duhok, Kurdistan Region, Iraq. The SwissTargetPrediction program was utilized in silico to predict and identify human body proteins that could be potentially targeted by selected medications involved in polypharmacy. Results All patients had tested positive for COVID-19 via PCR testing, and they showed different signs and symptoms of the disease. None of the patients recovered and all of them deceased. All 33 patients received many therapeutic agents that ranged in number from eight to 20/patient during their hospital stay. The mean number of medications was 15 ± 3. We identified 2/33 (6%) patients with major polypharmacy (eight and nine) and 31/33 (94%) with excessive polypharmacy (15.5 ± 2.7). The total number of medications identified in polypharmacy was 37, excluding vitamins, minerals, and intravenous solutions. The frequency of medications administered was as follows: antibiotics (67, 13.7%), mucolytic agents (56, 11.5%), corticosteroids (54, 11%), anticoagulants (48, 9.8%), antiviral agents (41, 8.4%), antihypertensive agents (32, 6.5%), analgesics (28, 5.7%), antifungal drugs (27, 5.5%), antidiabetics (26, 5.3%), and other medications (2-19, 0.41-3.9%). Using the SwissTargetPrediction program, various drugs including antiviral agents involved in polypharmacy were found to target, in silico, body proteins at a prediction percentage that ranged from 6.7% to 40%. Conclusions Major and extensive polypharmacy conditions were identified in hospitalized COVID-19 patients suffering from cytokine storm. The severity of COVID-19 with cytokine storm, comorbidities, and hospitalization were key factors associated with polypharmacy in the patients. The SwissTargetPrediction web server is useful for predicting in silico potential human body protein targets that could possibly be sources of additional information on the adverse/toxic effects of polypharmacy medications administered concurrently. Further research in current medication protocols prescribed for advanced COVID-19 illness with cytokine storm is warranted to gain deeper insights into the topic.
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Affiliation(s)
- Ghazwan A Raouf
- Department of Pharmacology, College of Pharmacy, University of Duhok, Duhok, IRQ
| | - Fouad K Mohammad
- Department of Physiology, Biochemistry and Pharmacology, College of Veterinary Medicine, University of Mosul, Mosul, IRQ
- College of Nursing, The American University of Kurdistan, Duhok, IRQ
| | - Muayad A Merza
- Department of Internal Medicine, University of Duhok, Duhok, IRQ
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Suhandi C, Alfathonah SS, Hasanah AN. Potency of Xanthone Derivatives from Garcinia mangostana L. for COVID-19 Treatment through Angiotensin-Converting Enzyme 2 and Main Protease Blockade: A Computational Study. Molecules 2023; 28:5187. [PMID: 37446849 DOI: 10.3390/molecules28135187] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2023] [Revised: 06/23/2023] [Accepted: 07/01/2023] [Indexed: 07/15/2023] Open
Abstract
ACE2 and Mpro in the pathology of SARS-CoV-2 show great potential in developing COVID-19 drugs as therapeutic targets, due to their roles as the "gate" of viral entry and viral reproduction. Of the many potential compounds for ACE2 and Mpro inhibition, α-mangostin is a promising candidate. Unfortunately, the potential of α-mangostin as a secondary metabolite with the anti-SARS-CoV-2 activity is hindered due to its low solubility in water. Other xanthone isolates, which also possess the xanthone core structure like α-mangostin, are predicted to be potential alternatives to α-mangostin in COVID-19 treatment, addressing the low drug-likeness of α-mangostin. This study aims to assess the potential of xanthone derivative compounds in the pericarp of mangosteen (Garcinia mangostana L.) through computational study. The study was conducted through screening activity using molecular docking study, drug-likeness prediction using Lipinski's rule of five filtration, pharmacokinetic and toxicity prediction to evaluate the safety profile, and molecular dynamic study to evaluate the stability of formed interactions. The research results showed that there were 11 compounds with high potential to inhibit ACE2 and 12 compounds to inhibit Mpro. However, only garcinone B, in addition to being indicated as active, also possesses a drug-likeness, pharmacokinetic, and toxicity profile that was suitable. The molecular dynamic study exhibited proper stability interaction between garcinone B with ACE2 and Mpro. Therefore, garcinone B, as a xanthone derivative isolate compound, has promising potential for further study as a COVID-19 treatment as an ACE2 and Mpro inhibitor.
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Affiliation(s)
- Cecep Suhandi
- Department Pharmaceutics and Pharmaceutical Technology, Faculty of Pharmacy, Universitas Padjadjaran, Sumedang 45363, Indonesia
- Department Pharmaceutical Analysis and Medicinal Chemistry, Faculty of Pharmacy, Universitas Padjadjaran, Sumedang 45363, Indonesia
| | - Siti Sarah Alfathonah
- Department Pharmaceutical Analysis and Medicinal Chemistry, Faculty of Pharmacy, Universitas Padjadjaran, Sumedang 45363, Indonesia
| | - Aliya Nur Hasanah
- Department Pharmaceutical Analysis and Medicinal Chemistry, Faculty of Pharmacy, Universitas Padjadjaran, Sumedang 45363, Indonesia
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Patel S, Hasan H, Umraliya D, Sanapalli BKR, Yele V. Marine drugs as putative inhibitors against non-structural proteins of SARS-CoV-2: an in silico study. J Mol Model 2023; 29:176. [PMID: 37171714 PMCID: PMC10176293 DOI: 10.1007/s00894-023-05574-9] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2022] [Accepted: 04/26/2023] [Indexed: 05/13/2023]
Abstract
INTRODUCTION Coronavirus disease 2019 (COVID-19) is an unprecedented pandemic, threatening human health worldwide. The need to produce novel small-molecule inhibitors against the ongoing pandemic has resulted in the use of drugs such as chloroquine, azithromycin, dexamethasone, favipiravir, ribavirin, remdesivir and azithromycin. Moreover, the reports of the clinical trials of these drugs proved to produce detrimental effects on patients with side effects like nephrotoxicity, retinopathy, cardiotoxicity and cardiomyopathy. Recognizing the need for effective and non-harmful therapeutic candidates to combat COVID-19, we aimed to develop promising drugs against SARS-COV-2. DISCUSSION In the current investigation, high-throughput virtual screening was performed using the Comprehensive Marine Natural Products Database against five non-structural proteins: Nsp3, Nsp5, Nsp12, Nsp13 and Nsp15. Furthermore, standard precision (SP) docking, extra precision (XP) docking, binding free energy calculation and absorption, distribution, metabolism, excretion and toxicity studies were performed using the Schrӧdinger suite. The top-ranked 5 hits obtained by computational studies exhibited to possess a greater binding affinity with the selected non-structural proteins. Amongst the five hits, CMNPD5804, CMNPD20924 and CMNPD1598 hits were utilized to design a novel molecule (D) that has the capability of interacting with all the key residues in the pocket of the selected non-structural proteins. Furthermore, 200 ns of molecular dynamics simulation studies provided insight into the binding modes of D within the catalytic pocket of selected proteins. CONCLUSION Hence, it is concluded that compound D could be a promising inhibitor against these non-structural proteins. Nevertheless, there is still a need to conduct in vitro and in vivo studies to support our findings.
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Affiliation(s)
- Simran Patel
- Faculty of Pharmacy, Marwadi University, Rajkot, Gujarat, 360003, India
| | - Haydara Hasan
- Faculty of Pharmacy, Marwadi University, Rajkot, Gujarat, 360003, India
| | - Divyesh Umraliya
- Faculty of Pharmacy, Marwadi University, Rajkot, Gujarat, 360003, India
| | - Bharat Kumar Reddy Sanapalli
- Department of Pharmacology, Faculty of Pharmacy, Marwadi University, Rajkot, Gujarat, 360003, India.
- Department of Pharmacology, School of Pharmaceutical Sciences, MB University, Tirupati, Andhra Pradesh, 517102, India.
| | - Vidyasrilekha Yele
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Marwadi University, Rajkot, Gujarat, 360003, India.
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Arrieta A, Galvis AE, Osborne S, Morphew T, Imfeld K, Enriquez C, Hoang J, Swearingen M, Nieves DJ, Ashouri N, Singh J, Nugent D. Use of COVID-19 Convalescent Plasma for Treatment of Symptomatic SARS-CoV-2 Infection at a Children's Hospital: A Contribution to a Still Inadequate Body of Evidence. CHILDREN (BASEL, SWITZERLAND) 2023; 10:children10020350. [PMID: 36832478 PMCID: PMC9955755 DOI: 10.3390/children10020350] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 12/01/2022] [Revised: 01/13/2023] [Accepted: 02/07/2023] [Indexed: 02/12/2023]
Abstract
Data on COVID-19 convalescent plasma (CCP) safety and efficacy in children and young adults are limited. This single-center prospective, open-label trial evaluates CCP safety, neutralizing antibody kinetics, and outcomes in children and young adults with moderate/severe COVID-19 (April 2020-March 2021). A total of 46 subjects received CCP; 43 were included in the safety analysis (SAS); 7.0% < 2 years old, 2.3% 2-<6, 27.9% 6-<12, 39.5% 12-<19, and 23.3% > 19 years old; 28 were included in the antibody kinetic analysis (AbKS); 10.7% < 2 years old, 10.7% 6-<12, 53.8% 12-<19, and 25.0% > 19 years old. No adverse events occurred. The median COVID-19 severity score improved (5.0 pre-CCP to 1.0 by day 7; p < 0.001). A rapid increase in the median percentage of inhibition was observed in AbKS (22.5% (13.0%, 41.5%) pre-infusion to 52% (23.7%, 72%) 24 h post-infusion); a similar increase was observed in nine immune-competent subjects (28% (23%, 35%) to 63% (53%, 72%)). The inhibition percentage increased until day 7 and persisted at 21 and 90 days. CCP is well tolerated in children and young adults, providing rapid and robust increased antibodies. CCP should remain a therapeutic option for this population for whom vaccines are not fully available and given that the safety and efficacy of existing monoclonal antibodies and antiviral agents have not been established.
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Affiliation(s)
- Antonio Arrieta
- Pediatrics Infectious Diseases, CHOC Children’s Hospital, Orange, CA 92868, USA
- Department of Pediatrics, University of California Irvine School of Medicine, Irvine, CA 92697, USA
| | - Alvaro E. Galvis
- Pediatrics Infectious Diseases, CHOC Children’s Hospital, Orange, CA 92868, USA
- Department of Pediatrics, University of California Irvine School of Medicine, Irvine, CA 92697, USA
| | - Stephanie Osborne
- Research Administration, CHOC Children’s Hospital, Orange, CA 92868, USA
| | - Tricia Morphew
- Morphew Consulting, LLC, CHOC Research Institute, CHOC Children’s Hospital, Orange, CA 92868, USA
| | - Karen Imfeld
- Hematology Advanced Diagnostics Laboratory, CHOC Children’s Hospital, Orange, CA 92868, USA
| | - Claudia Enriquez
- Research Administration, CHOC Children’s Hospital, Orange, CA 92868, USA
| | - Janet Hoang
- Hematology Advanced Diagnostics Laboratory, CHOC Children’s Hospital, Orange, CA 92868, USA
| | - Marcia Swearingen
- Hematology Advanced Diagnostics Laboratory, CHOC Children’s Hospital, Orange, CA 92868, USA
| | - Delma J. Nieves
- Pediatrics Infectious Diseases, CHOC Children’s Hospital, Orange, CA 92868, USA
- Department of Pediatrics, University of California Irvine School of Medicine, Irvine, CA 92697, USA
- Correspondence: ; Tel.: +714-509-8403; Fax: +714-509-3303
| | - Negar Ashouri
- Pediatrics Infectious Diseases, CHOC Children’s Hospital, Orange, CA 92868, USA
- Department of Pediatrics, University of California Irvine School of Medicine, Irvine, CA 92697, USA
| | - Jasjit Singh
- Pediatrics Infectious Diseases, CHOC Children’s Hospital, Orange, CA 92868, USA
- Department of Pediatrics, University of California Irvine School of Medicine, Irvine, CA 92697, USA
| | - Diane Nugent
- Department of Pediatrics, University of California Irvine School of Medicine, Irvine, CA 92697, USA
- Pediatric Hematology, CHOC Children’s Hospital, Orange, CA 92868, USA
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Plant Spices as a Source of Antimicrobial Synergic Molecules to Treat Bacterial and Viral Co-Infections. MOLECULES (BASEL, SWITZERLAND) 2022; 27:molecules27238210. [PMID: 36500303 PMCID: PMC9737474 DOI: 10.3390/molecules27238210] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 10/28/2022] [Revised: 11/19/2022] [Accepted: 11/22/2022] [Indexed: 11/27/2022]
Abstract
The COVID-19 pandemic exposed the lack of antiviral agents available for human use, while the complexity of the physiological changes caused by coronavirus (SARS-CoV-2) imposed the prescription of multidrug pharmacotherapy to treat infected patients. In a significant number of cases, it was necessary to add antibiotics to the prescription to decrease the risk of co-infections, preventing the worsening of the patient's condition. However, the precautionary use of antibiotics corroborated to increase bacterial resistance. Since the development of vaccines for COVID-19, the pandemic scenario has changed, but the development of new antiviral drugs is still a major challenge. Research for new drugs with synergistic activity against virus and resistant bacteria can produce drug leads to be used in the treatment of mild cases of COVID-19 and to fight other viruses and new viral diseases. Following the repurposing approach, plant spices have been searched for antiviral lead compounds, since the toxic effects of plants that are traditionally consumed are already known, speeding up the drug discovery process. The need for effective drugs in the context of viral diseases is discussed in this review, with special focus on plant-based spices with antiviral and antibiotic activity. The activity of plants against resistant bacteria, the diversity of the components present in plant extracts and the synergistic interaction of these metabolites and industrialized antibiotics are discussed, with the aim of contributing to the development of antiviral and antibiotic drugs. A literature search was performed in electronic databases such as Science Direct; SciELO (Scientific Electronic Library Online); LILACS (Latin American and Caribbean Literature on Health Sciences); Elsevier, SpringerLink; and Google Scholar, using the descriptors: antiviral plants, antibacterial plants, coronavirus treatment, morbidities and COVID-19, bacterial resistance, resistant antibiotics, hospital-acquired infections, spices of plant origin, coronaviruses and foods, spices with antiviral effect, drug prescriptions and COVID-19, and plant synergism. Articles published in English in the period from 2020 to 2022 and relevant to the topic were used as the main inclusion criteria.
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Jansen-van Vuuren RD, Jedlovčnik L, Košmrlj J, Massey TE, Derdau V. Deuterated Drugs and Biomarkers in the COVID-19 Pandemic. ACS OMEGA 2022; 7:41840-41858. [PMID: 36440130 PMCID: PMC9685803 DOI: 10.1021/acsomega.2c04160] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/02/2022] [Accepted: 10/18/2022] [Indexed: 06/07/2023]
Abstract
Coronavirus disease 2019 (COVID-19) is a highly contagious disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Initially identified in Wuhan (China) in December 2019, COVID-19 rapidly spread globally, resulting in the COVID-19 pandemic. Carriers of the SARS-CoV-2 can experience symptoms ranging from mild to severe (or no symptoms whatsoever). Although vaccination provides extra immunity toward SARS-CoV-2, there has been an urgent need to develop treatments for COVID-19 to alleviate symptoms for carriers of the disease. In seeking a potential treatment, deuterated compounds have played a critical role either as therapeutic agents or as internal MS standards for studying the pharmacological properties of new drugs by quantifying the parent compounds and metabolites. We have identified >70 examples of deuterium-labeled compounds associated with treatment of COVID-19. Of these, we found 9 repurposed drugs and >20 novel drugs studied for potential therapeutic roles along with a total of 38 compounds (drugs, biomarkers, and lipids) explored as internal mass spectrometry standards. This review details the synthetic pathways and modes of action of these compounds (if known), and a brief analysis of each study.
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Affiliation(s)
- Ross D. Jansen-van Vuuren
- Faculty
of Chemistry and Chemical Technology, University
of Ljubljana, Večna pot 113, Ljubljana 1000, Slovenia
- Department
of Chemistry, Queen’s University, 90 Bader Lane, Kingston, Ontario K7L
3N6, Canada
| | - Luka Jedlovčnik
- Faculty
of Chemistry and Chemical Technology, University
of Ljubljana, Večna pot 113, Ljubljana 1000, Slovenia
| | - Janez Košmrlj
- Faculty
of Chemistry and Chemical Technology, University
of Ljubljana, Večna pot 113, Ljubljana 1000, Slovenia
| | - Thomas E. Massey
- Department
of Biomedical and Molecular Sciences, School of Medicine, Queen’s University, Botterell Hall, 18 Stuart Street, Kingston, Ontario K7L 3N6, Canada
| | - Volker Derdau
- Research
& Development, Integrated Drug Discovery, Isotope Chemistry, Sanofi-Aventis Deutschland GmbH, Industriepark Höchst G876, Frankfurt/Main 65926, Germany
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Ruiz HK, Serrano DR, Calvo L, Cabañas A. Current Treatments for COVID-19: Application of Supercritical Fluids in the Manufacturing of Oral and Pulmonary Formulations. Pharmaceutics 2022; 14:2380. [PMID: 36365198 PMCID: PMC9697571 DOI: 10.3390/pharmaceutics14112380] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2022] [Revised: 10/23/2022] [Accepted: 10/28/2022] [Indexed: 10/06/2024] Open
Abstract
Even though more than two years have passed since the emergence of COVID-19, the research for novel or repositioned medicines from a natural source or chemically synthesized is still an unmet clinical need. In this review, the application of supercritical fluids to the development of novel or repurposed medicines for COVID-19 and their secondary bacterial complications will be discussed. We envision three main applications of the supercritical fluids in this field: (i) drug micronization, (ii) supercritical fluid extraction of bioactives and (iii) sterilization. The supercritical fluids micronization techniques can help to improve the aqueous solubility and oral bioavailability of drugs, and consequently, the need for lower doses to elicit the same pharmacological effects can result in the reduction in the dose administered and adverse effects. In addition, micronization between 1 and 5 µm can aid in the manufacturing of pulmonary formulations to target the drug directly to the lung. Supercritical fluids also have enormous potential in the extraction of natural bioactive compounds, which have shown remarkable efficacy against COVID-19. Finally, the successful application of supercritical fluids in the inactivation of viruses opens up an opportunity for their application in drug sterilization and in the healthcare field.
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Affiliation(s)
- Helga K. Ruiz
- Department of Physical Chemistry, Complutense University of Madrid, 28040 Madrid, Spain
| | - Dolores R. Serrano
- Department of Pharmaceutics and Food Technology, Complutense University of Madrid, 28040 Madrid, Spain
| | - Lourdes Calvo
- Department of Chemical Engineering, Complutense University of Madrid, 28040 Madrid, Spain
| | - Albertina Cabañas
- Department of Physical Chemistry, Complutense University of Madrid, 28040 Madrid, Spain
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Aleissa MS, AL-Zharani M, Hasnain MS, Alkahtani S. Screening, molecular simulation & in silico kinetics of virtually designed covid-19 main protease inhibitors. JOURNAL OF KING SAUD UNIVERSITY - SCIENCE 2022; 34:102283. [PMID: 36062199 PMCID: PMC9428119 DOI: 10.1016/j.jksus.2022.102283] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/10/2022] [Revised: 05/27/2022] [Accepted: 08/13/2022] [Indexed: 11/07/2022]
Abstract
Coronavirus (covid-19) infection is considered to be deadliest ever pandemic experienced by the human being. It has very badly affected the socio-economic health of human and stuck the scientific community to think and rethink about its complete eradication. But due to no effective treatment or unavailability of vaccine the health professional could not show any significant improvement to control the pandemic. The situation needs newer molecule, vaccine or effective treatment to control covid-19 infection. Different target in viruses has been explored and proteases enzymes were found to be therapeutically effective target for the design of potential anti-covid-19 molecule as it plays the vital role in viral replication and assembly. Structure-based drug design was employed to discover the small molecule of anti-covid-19. Here we considered the small library of naturally occurring polyphenolic compounds and molecular docking, Molecular dynamics (MD) simulations, free binding energy calculation and in-silico ADME calculations to identify the newer HITs. Based upon their score the two molecules were identified as promising candidate. The docking scores were found to be −7.643 and −7.065 for the HIT1 and HIT-2 respectively. In MD simulations study the RMSD values were found to be 4.3 Å & 4.9 Å respectively. To validate these results MM-GBSA was performed and their binding free energies were computationally determined. The prime energy values of identified HITs (−13412.45 & −13441.8 kJ/mole) were found to be very close proximity to reference molecule (−13493.05 kJ/mole). Then in-silico ADME calculations were performed to calculate the drug likeliness identified HITs. BY considering all the values comparative to reference molecule and obtained in-silico pharmacokinetic properties of identified HITs we can suggest that HIT-1 and HIT-2 would be the most promising molecules that can inhibit the main protease enzyme of covid-19. These two molecules would become the potential drug candidate for the treatment of covid-19 infections.
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Aljarba NH, Hasnain MS, Bin-Meferij MM, Alkahtani S. An in-silico investigation of potential natural polyphenols for the targeting of COVID main protease inhibitor. JOURNAL OF KING SAUD UNIVERSITY. SCIENCE 2022; 34:102214. [PMID: 35811756 PMCID: PMC9250415 DOI: 10.1016/j.jksus.2022.102214] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/16/2022] [Revised: 06/07/2022] [Accepted: 06/28/2022] [Indexed: 05/04/2023]
Abstract
The deadliest recent pandemic outbreak of COVID-19 disease has severely damaged the socio-economic health of the people globally. Due to unavailability of any effective vaccine or treatment the human beings are still struggling to overcome the pandemic condition. In an attempt to discover anti-COVID molecule, we used in-silico approach and reported 160 natural polyphenols to identify the most promising druggable HITs that can further used for drug discovery process. The co-crystallized structure COVID protease enzyme (PDB id 6LU7) was used. HTVS, MD simulation, binding energy calculations and in-silico ADME calculation were done and analyzed. Depending upon the scores three compounds galangin, nalsudaldain and rhamnezine were identified and the docking score were found to be -7.704, -6.51, -4.212 respectively. These docked complexes were further subjected to MD simulation runs over a 100 ns time and the RMSD and RMSF values were determined. The RMSD values of three compounds were found to be 2.9 Å, 7.6 Å & 9.5 Å respectively and the lowest RMSF values suggested the steady stability of ligand-protein complexes. The binding free energies (ΔG) of compounds with protein were found to be -49.8, -56.45, -62.87 kJ/mole. Moreover, in-silico ADME calculations indicated the drug likeliness properties of these molecules. By considering all these in-silico results the identified HITs would be the most probable anti-COVID drug molecules that can be further taken in wet lab and can act as lead for development of newer inhibitor of COVID-19 main protease enzyme.
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Affiliation(s)
- Nada H Aljarba
- Department of Biology, College of Science, Princess Nourah bint Abdulrahman University, Riyadh, Saudi Arabia
| | - Md Saquib Hasnain
- Department of Pharmacy, Palamau Institute of Pharmacy, Chianki, Daltonganj 822102, Jharkhand, India
| | | | - Saad Alkahtani
- Department of Zoology, College of Science, King Saud University, P. O. Box 2455, Riyadh 11451, Saudi Arabia
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12
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Xu H, Liu G, Gong J, Zhang Y, Gu S, Wan Z, Yang P, Nie Y, Wang Y, Huang Z, Luo G, Chen Z, Zhang D, Cao N. Investigating and Resolving Cardiotoxicity Induced by COVID-19 Treatments using Human Pluripotent Stem Cell-Derived Cardiomyocytes and Engineered Heart Tissues. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2022; 9:e2203388. [PMID: 36055796 PMCID: PMC9539280 DOI: 10.1002/advs.202203388] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/10/2022] [Revised: 08/09/2022] [Indexed: 05/04/2023]
Abstract
Coronavirus disease 2019 continues to spread worldwide. Given the urgent need for effective treatments, many clinical trials are ongoing through repurposing approved drugs. However, clinical data regarding the cardiotoxicity of these drugs are limited. Human pluripotent stem cell-derived cardiomyocytes (hCMs) represent a powerful tool for assessing drug-induced cardiotoxicity. Here, by using hCMs, it is demonstrated that four antiviral drugs, namely, apilimod, remdesivir, ritonavir, and lopinavir, exhibit cardiotoxicity in terms of inducing cell death, sarcomere disarray, and dysregulation of calcium handling and contraction, at clinically relevant concentrations. Human engineered heart tissue (hEHT) model is used to further evaluate the cardiotoxic effects of these drugs and it is found that they weaken hEHT contractile function. RNA-seq analysis reveals that the expression of genes that regulate cardiomyocyte function, such as sarcomere organization (TNNT2, MYH6) and ion homeostasis (ATP2A2, HCN4), is significantly altered after drug treatments. Using high-throughput screening of approved drugs, it is found that ceftiofur hydrochloride, astaxanthin, and quetiapine fumarate can ameliorate the cardiotoxicity of remdesivir, with astaxanthin being the most prominent one. These results warrant caution and careful monitoring when prescribing these therapies in patients and provide drug candidates to limit remdesivir-induced cardiotoxicity.
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Affiliation(s)
- He Xu
- Center of Translational MedicineThe First Affiliated HospitalZhongshan School of MedicineSun Yat‐Sen UniversityGuangdong510080China
- NHC Key Laboratory of Assisted Circulation (Sun Yat‐Sen University)Guangzhou510080China
| | - Ge Liu
- The Seventh Affiliated HospitalZhongshan School of MedicineSun Yat‐Sen UniversityGuangdong510080China
| | - Jixing Gong
- National & Local Joint Engineering Research Center of High‐throughput Drug Screening TechnologyState Key Laboratory of Biocatalysis and Enzyme EngineeringHubei Province Key Laboratory of Biotechnology of Chinese Traditional MedicineHubei UniversityWuhan430062China
| | - Ying Zhang
- The Seventh Affiliated HospitalZhongshan School of MedicineSun Yat‐Sen UniversityGuangdong510080China
- MOE Key Laboratory of Gene Function and RegulationState Key Laboratory of BiocontrolSchool of Life SciencesSun Yat‐Sen UniversityGuangdong510275China
| | - Shanshan Gu
- The Seventh Affiliated HospitalZhongshan School of MedicineSun Yat‐Sen UniversityGuangdong510080China
| | - Zhongjun Wan
- National & Local Joint Engineering Research Center of High‐throughput Drug Screening TechnologyState Key Laboratory of Biocatalysis and Enzyme EngineeringHubei Province Key Laboratory of Biotechnology of Chinese Traditional MedicineHubei UniversityWuhan430062China
| | - Pengcheng Yang
- National & Local Joint Engineering Research Center of High‐throughput Drug Screening TechnologyState Key Laboratory of Biocatalysis and Enzyme EngineeringHubei Province Key Laboratory of Biotechnology of Chinese Traditional MedicineHubei UniversityWuhan430062China
| | - Yage Nie
- The Seventh Affiliated HospitalZhongshan School of MedicineSun Yat‐Sen UniversityGuangdong510080China
| | - Yinghan Wang
- The Seventh Affiliated HospitalZhongshan School of MedicineSun Yat‐Sen UniversityGuangdong510080China
| | - Zhan‐peng Huang
- Center of Translational MedicineThe First Affiliated HospitalZhongshan School of MedicineSun Yat‐Sen UniversityGuangdong510080China
- NHC Key Laboratory of Assisted Circulation (Sun Yat‐Sen University)Guangzhou510080China
| | - Guanzheng Luo
- MOE Key Laboratory of Gene Function and RegulationState Key Laboratory of BiocontrolSchool of Life SciencesSun Yat‐Sen UniversityGuangdong510275China
| | - Zhongyan Chen
- The Seventh Affiliated HospitalZhongshan School of MedicineSun Yat‐Sen UniversityGuangdong510080China
| | - Donghui Zhang
- National & Local Joint Engineering Research Center of High‐throughput Drug Screening TechnologyState Key Laboratory of Biocatalysis and Enzyme EngineeringHubei Province Key Laboratory of Biotechnology of Chinese Traditional MedicineHubei UniversityWuhan430062China
| | - Nan Cao
- The Seventh Affiliated HospitalZhongshan School of MedicineSun Yat‐Sen UniversityGuangdong510080China
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13
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Sathish JG, Bhatt S, DaSilva JK, Flynn D, Jenkinson S, Kalgutkar AS, Liu M, Manickam B, Pinkstaff J, Reagan WJ, Shirai N, Shoieb AM, Sirivelu M, Vispute S, Vitsky A, Walters K, Wisialowski TA, Updyke LW. Comprehensive Nonclinical Safety Assessment of Nirmatrelvir Supporting Timely Development of the SARS-COV-2 Antiviral Therapeutic, Paxlovid™. Int J Toxicol 2022; 41:276-290. [PMID: 35603517 PMCID: PMC9125132 DOI: 10.1177/10915818221095489] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022]
Abstract
COVID-19 is a potentially fatal infection caused by the SARS-CoV-2 virus. The SARS-CoV-2 3CL protease (Mpro) is a viral enzyme essential for replication and is the target for nirmatrelvir. Paxlovid (nirmatrelvir co-administered with the pharmacokinetic enhancer ritonavir) showed efficacy in COVID-19 patients at high risk of progressing to hospitalization and/or death. Nonclinical safety studies with nirmatrelvir are essential in informing benefit-risk of Paxlovid and were conducted to support clinical development. In vivo safety pharmacology assessments included a nervous system/pulmonary study in rats and a cardiovascular study in telemetered monkeys. Potential toxicities were assessed in repeat dose studies of up to 1 month in rats and monkeys. Nirmatrelvir administration (1,000 mg/kg, p.o.) to male rats produced transient increases in locomotor activity and respiratory rate but did not affect behavioral endpoints in the functional observational battery. Cardiovascular effects in monkeys were limited to transient increases in blood pressure and decreases in heart rate, observed only at the highest dose tested (75 mg/kg per dose b.i.d; p.o.). Nirmatrelvir did not prolong QTc-interval or induce arrhythmias. There were no adverse findings in repeat dose toxicity studies up to 1 month in rats (up to 1,000 mg/kg daily, p.o.) or monkeys (up to 600 mg/kg daily, p.o.). Nonadverse, reversible clinical pathology findings without clinical or microscopic correlates included prolonged coagulation times at ≥60 mg/kg in rats and increases in transaminases at 600 mg/kg in monkeys. The safety pharmacology and nonclinical toxicity profiles of nirmatrelvir support clinical development and use of Paxlovid for treatment of COVID-19.
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Affiliation(s)
- Jean G. Sathish
- Pfizer Worldwide Research, Development and Medical, Pfizer Inc, Pearl River, NY, USA
| | - Siddhartha Bhatt
- Pfizer Worldwide Research, Development and Medical, Pfizer Inc, Groton, CT, USA
| | - Jamie K. DaSilva
- Pfizer Worldwide Research, Development and Medical, Pfizer Inc, Groton, CT, USA
| | - Declan Flynn
- Pfizer Worldwide Research, Development and Medical, Pfizer Inc, Groton, CT, USA
| | - Stephen Jenkinson
- Pfizer Worldwide Research, Development and Medical, Pfizer Inc, San Diego, CA, USA
| | - Amit S. Kalgutkar
- Pfizer Worldwide Research, Development and Medical, Pfizer Inc, Cambridge, MA, USA
| | - Maggie Liu
- Pfizer Worldwide Research, Development and Medical, Pfizer Inc, San Diego, CA, USA
| | | | - Jason Pinkstaff
- Pfizer Worldwide Research, Development and Medical, Pfizer Inc, San Diego, CA, USA
| | - William J. Reagan
- Pfizer Worldwide Research, Development and Medical, Pfizer Inc, Groton, CT, USA
| | - Norimitsu Shirai
- Pfizer Worldwide Research, Development and Medical, Pfizer Inc, Groton, CT, USA
| | - Ahmed M. Shoieb
- Pfizer Worldwide Research, Development and Medical, Pfizer Inc, Groton, CT, USA
| | - Madhu Sirivelu
- Pfizer Worldwide Research, Development and Medical, Pfizer Inc, Cambridge, MA, USA
| | - Saurabh Vispute
- Pfizer Worldwide Research, Development and Medical, Pfizer Inc, Groton, CT, USA
| | - Allison Vitsky
- Pfizer Worldwide Research, Development and Medical, Pfizer Inc, San Diego, CA, USA
| | - Karen Walters
- Pfizer Worldwide Research, Development and Medical, Pfizer Inc, Groton, CT, USA
| | - Todd A. Wisialowski
- Pfizer Worldwide Research, Development and Medical, Pfizer Inc, Groton, CT, USA
| | - Lawrence W. Updyke
- Pfizer Worldwide Research, Development and Medical, Pfizer Inc, Cambridge, MA, USA
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14
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Durgam L, Guruprasad L. Computational studies on the design of NCI natural products as inhibitors to SARS-CoV-2 main protease. J Biomol Struct Dyn 2022; 41:3741-3751. [PMID: 35333147 DOI: 10.1080/07391102.2022.2054470] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
The pandemic coronavirus disease (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has resulted in more than 5 million deaths globally. Currently there are no effective drugs available to treat COVID-19. The viral protease replication can be blocked by the inhibition of main protease that is encoded in polyprotein 1a and is therefore a potential protein target for drug discovery. We have carried out virtual screening of NCI natural compounds followed by molecular docking in order to identify hit molecules as probable SARS-CoV-2 main protease inhibitors. The molecular dynamics (MD) simulations of apo form in complex with N3, α-ketoamide and NCI natural products was used to validate the screened compounds. The MD simulations trajectories were analyzed using normal mode analysis and principal component analysis revealing dynamical nature of the protein. These findings aid in understanding the binding of natural products and molecular mechanisms of SARS-CoV-2 main protease inhibition.Communicated by Ramaswamy H. Sarma.
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Affiliation(s)
- Laxman Durgam
- School of Chemistry, University of Hyderabad, Hyderabad, India
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15
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Yaghoubifard S, Hashemi-Meshkini A, Koochak R, Nikfar S, Rezaei-Darzi E. Evaluation of COVID-19 treatments in Iran in comparison with local therapeutic recommendations: A population-level study on utilization and costs of prescription drugs. J Res Pharm Pract 2022; 11:1-7. [PMID: 36277970 PMCID: PMC9585804 DOI: 10.4103/jrpp.jrpp_6_22] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2022] [Accepted: 04/07/2022] [Indexed: 11/06/2022] Open
Abstract
Objective: In this study, we assess population-level data of COVID-19 treatments in Iran compared to Ministry of Health (MOH)-published guidelines to gain a better insight into the quality of care for this disease. Methods: National sales data of each recommended and nonrecommended COVID-19 medicine were used to proxy utilization between March 21, 2020, and March 21, 2021, or Iranian year 1399. COVID-19–attributed sales volume and number of patients were estimated by adjusting sales data with pre-COVID-19 average growth rate, recommended dose, and duration of treatment. Next, they were compared with the MOH guidelines in outpatient and inpatient settings. Furthermore, the list of top 10 molecules of the market and top 10 COVID-19–indicated molecules in terms of values were extracted to assess the economic burden of COVID-19 prescription drugs and their share. Findings: The estimated number of patients receiving COVID-19 treatments in some outpatient medicines such as recommended hydroxychloroquine was over 2.2 million. Favipiravir and remdesivir were collectively about two inpatient medicines 260,000; however, neither of these two medicines was recommended in the MOH guidelines. In some fewer specific medicines such as dexamethasone, prednisolone, azithromycin, and naproxen, the estimated number of COVID-19–attributed patients were incomparable with the officially announced number of confirmed cases in the year of study, which could be related to nonconfirmed diagnosed cases, irrational use, or prescribing, or limitations of our data and study. The total COVID-19–attributed market of candidate medicines was over 15 trillion IR Rials (almost 4.3% of the total market). Remdesivir, with over 60% of the total COVID-19 attributed market, followed by favipiravir, was among the highest value medicines. Conclusion: Despite the release of the COVID-19 guideline by Iran MOH, misalignment in the enforcement of decisions was a serious weakness (cases of favipiravir and remdesivir). This weakness led to some economic burden on the health-care system and raised ethical concerns.
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16
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Freidel M, Armen RS. Modeling the Structure-Activity Relationship of Arbidol Derivatives and Other SARS-CoV-2 Fusion Inhibitors Targeting the S2 Segment of the Spike Protein. J Chem Inf Model 2021; 61:5906-5922. [PMID: 34898207 PMCID: PMC8691200 DOI: 10.1021/acs.jcim.1c01061] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
Umifenovir (Arbidol) has been reported to exhibit some degree of efficacy in multiple clinical trials for the treatment of COVID-19 as a monotherapy. It has also demonstrated synergistic inhibition of SARS-CoV-2 with other direct-acting antivirals such as Remdesivir. A computational approach was used to identify the most favorable binding site to the SARS-CoV-2 Spike S2 segment and to perform virtual screening. Compounds selected from modeling were evaluated in a live SARS-CoV-2 infection assay. An Arbidol (ARB) derivative with substitutions at both the C-4 and C-6 positions was found to exhibit a modest improvement in activity and solubility properties in comparison to ARB. However, all of the derivatives were found to only be partial inhibitors, rather than full inhibitors in a virus-induced cytopathic effect-based assay. The binding mode is also corroborated by parallel modeling of a series of oleanolic acid trisaccharide saponin fusion inhibitors shown to bind to the S2 segment. Recently determined experimental structures of the Spike protein allowed atomic resolution modeling of fusion inhibitor binding as a function of pH, and the implications for the molecular mechanism of direct-acting fusion inhibitors targeting the S2 segment are discussed.
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Affiliation(s)
- Matthew
R. Freidel
- Department of Pharmaceutical
Sciences, College of Pharmacy, Thomas Jefferson
University, 901 Walnut St. Suite 918, Philadelphia, Pennsylvania 19170, United States
| | - Roger S. Armen
- Department of Pharmaceutical
Sciences, College of Pharmacy, Thomas Jefferson
University, 901 Walnut St. Suite 918, Philadelphia, Pennsylvania 19170, United States
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17
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Trukhan DI, Davydov EL. Liver drug damage: possibilities of polyionic succinate-methioninic complex during the pandemic of new coronavirus infection (COVID-19). MEDITSINSKIY SOVET = MEDICAL COUNCIL 2021:110-121. [DOI: 10.21518/2079-701x-2021-15-110-121] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/02/2025]
Abstract
Medicinal liver damage is an important problem not only in the framework of hepatology and gastroenterology, but also for internal medicine in general, which is due to the difficulties of correct and timely diagnosis of this pathology. In the first part of the review, the main mechanisms of liver tissue damage and clinical and formological manifestations of drug-induced liver damage are considered.The pandemic of the new coronavirus infection (COVID-19), spread by the SARS-CoV-2 virus, has become a challenge to health systems around the world. The global clinical experience gained over the past year in the management of patients with a new coronavirus infection makes it possible to highlight a number of relevant clinical aspects, one of which is drug-induced liver damage associated with the treatment of COVID-19. In the second part of the review, the possible mechanisms of influence of COVID-19 on the hepatobiliary system are considered, which include viral cytotoxicity, a secondary effect of immune dysregulation; hypoxia as a result of respiratory failure and subsequent ischemic liver damage; reactivation of already existing liver pathology and drug damage to the liver. It has been established that a large number of drugs used to treat COVID-19 - antiviral agents, antibacterials, non-steroidal anti-inflammatory drugs, steroids and others - have hepatoxic effects and can cause liver damage. In the context of the COVID-19 pandemic, for patients with a new coronavirus infection and drug-induced liver damage, a rational, pathogenetically justified choice of a hepatoprotective drug is of particular importance. In the final part of the review, the possibilities of the polyionic succinate-methionine complex in the treatment of drug-induced liver damage are considered and a clinical example of the drug application in a patient with drug-induced liver damage during treatment with COVID-19 is given.
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Affiliation(s)
| | - E. L. Davydov
- Krasnoyarsk State Medical University named after Professor V.F. Voino-Yasenetsky
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18
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Rasouli M, Vakilian F, Ranjbari J. Therapeutic and protective potential of mesenchymal stem cells, pharmaceutical agents and current vaccines against covid-19. Curr Stem Cell Res Ther 2021; 17:166-185. [PMID: 33349221 DOI: 10.2174/1574888x16666201221151853] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2021] [Revised: 07/07/2021] [Accepted: 07/19/2021] [Indexed: 11/22/2022]
Abstract
It has been almost 18 months since the first outbreak of COVID-19 disease was reported in Wuhan, China. This unexpected devastating phenomenon, raised a great deal of concerns and anxiety among people around the world and imposed a huge economic burden on the nations' health care systems. Accordingly, clinical scientists, pharmacologists and physicians worldwide felt an urgent demand for a safe, effective therapeutic agent, treatment strategy or vaccine in order to prevent or cure the recently-emerged disease. Initially, due to lack of specific pharmacological agents and approved vaccines to combat the COVID-19, the disease control in the confirmed cases was limited to supportive care. Accordingly, repositioning or repurposing current drugs and examining their possible therapeutic efficacy received a great deal of attention. Despite revealing promising results in some clinical trials, the overall results are conflicting. For this reason, there is an urgent to seek and investigate other potential therapeutics. Mesenchymal stem cells (MSC) representing immunomodulatory and regenerative capacity to treat both curable and intractable diseases, have been investigated in COVID-19 clinical trials carried out in different parts of the world. Nevertheless, up to now, none of MSC-based approaches has been approved in controlling COVID-19 infection. Thanks to the fact that the final solution for defeating the pandemic is developing a safe, effective vaccine, enormous efforts and clinical research have been carried out. In this review, we will concisely discuss the safety and efficacy of the most relevant pharmacological agents, MSC-based approaches and candidate vaccines for treating and preventing COVID-19 infection.
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Affiliation(s)
- Mehdi Rasouli
- Department of Tissue Engineering and Applied Cell Sciences, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran. Iran
| | | | - Javad Ranjbari
- Department of Medical Biotechnology, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran. Iran
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19
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Oh PS, Kang KW, Ryu SR, Lim S, Sohn MH, Lee SM, Jeong HJ. Evaluation of Photobiogoverning Role of Blue Light Irradiation on Viral Replication. Photochem Photobiol 2021; 98:461-470. [PMID: 34486753 DOI: 10.1111/php.13514] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2021] [Revised: 06/01/2021] [Accepted: 09/02/2021] [Indexed: 11/29/2022]
Abstract
Most recently, severe acute respiratory syndrome coronavirus-2 has triggered a global pandemic without successful therapeutics. The goal of the present study was to define the antiviral effect and therapeutic action of blue light irradiation in SARS-CoV-2-infected cells. Vero cells were infected with SARS-CoV-2 (NCCP43326) or mock inoculum at 50 pfu/well. After blue light irradiation, the inhibitory effect was assessed by qPCR and plaque reduction assay. When Vero cells were irradiated to blue light ranging from 1.6 to 10 J cm-2 , SARS-CoV-2 replication was inhibited by up to 80%. The antiviral effect of blue light irradiation was associated with translation suppression via the phosphorylation of eIF2α by prolonging endoplasmic reticulum (ER) stress. The levels of LC3A/B and Beclin-1, which are key markers of autophagy, and the levels of PERK and PDI for ER stress were highly increased, whereas caspase-3 cleavage was inhibited after blue light irradiation in the later stage of infection. Our data revealed that blue light irradiation exerted antiviral and photo-biogoverning activities by prolonging ER stress and stimulating autophagy progression during viral infection. The findings increase our understanding of how photo-energy acts on viral progression and have implications for use in therapeutic strategies against COVID-19.
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Affiliation(s)
- Phil-Sun Oh
- Department of Nuclear Medicine, Molecular Imaging & Therapeutic Medicine Research Center, Biomedical Research Institute, Jeonbuk National University Medical School and Hospital, Jeonju, Korea
| | - Kyung Won Kang
- Division of Biotechnology, College of Environmental and Bioresources, Jeonbuk National University, Iksan, Korea
| | - Seung Rok Ryu
- Division of Biotechnology, College of Environmental and Bioresources, Jeonbuk National University, Iksan, Korea
| | - SeokTae Lim
- Department of Nuclear Medicine, Molecular Imaging & Therapeutic Medicine Research Center, Biomedical Research Institute, Jeonbuk National University Medical School and Hospital, Jeonju, Korea
| | - Myung-Hee Sohn
- Department of Nuclear Medicine, Molecular Imaging & Therapeutic Medicine Research Center, Biomedical Research Institute, Jeonbuk National University Medical School and Hospital, Jeonju, Korea
| | - Sang-Myeong Lee
- Division of Biotechnology, College of Environmental and Bioresources, Jeonbuk National University, Iksan, Korea.,Laboratory of Veterinary Virology, College of Veterinary Medicine, Chungbuk National University, Cheongju, Korea
| | - Hwan-Jeong Jeong
- Department of Nuclear Medicine, Molecular Imaging & Therapeutic Medicine Research Center, Biomedical Research Institute, Jeonbuk National University Medical School and Hospital, Jeonju, Korea
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20
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Liu F, Liu H, Yu WY, Liu Z, Zhang X, Wang Y, Miao LB, Li ZY, Huang JS, Bao JF. The Associations of Lymphocyte Ratio and Neutrophil Ratio on Liver Dysfunction in COVID-19 Patients. Front Immunol 2021; 12:717461. [PMID: 34552588 PMCID: PMC8450365 DOI: 10.3389/fimmu.2021.717461] [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: 05/31/2021] [Accepted: 08/16/2021] [Indexed: 01/08/2023] Open
Abstract
Data on the impact of lymphocytes and neutrophils on the incidence of liver dysfunction in COVID-19 patients are limited. This study aimed to investigate the lateral and longitudinal associations of lymphocyte ratio (LR) and neutrophil ratio (NR) on liver dysfunction in COVID-19 patients. We tested 1,409 blood samples from 245 COVID-19 patients in China between January 2020 and June 2021. The lateral U-shaped relationships, determined by smooth curve fitting and the piecewise-linear mixed-effect model, were observed between LR, NR, and AST and the incidence of AST-linked liver dysfunction, with the threshold cutoffs of 26.1 and 62.0, respectively. Over the 1,409 tests, the LR ≤ 26.1 and NR ≥ 62.0 related to the occurrence of mild liver dysfunction (HR: 1.36; 95% CI: 1.01, 1.82), moderate liver dysfunction (HR: 1.37; 95% CI: 1.01, 1.85), and severe liver dysfunction (HR: 1.72; 95% CI: 1.02, 2.90). For the patients with preexisting AST ≥ 35 U/L, the baseline LR ≤ 26.1 and NR ≥ 62.0 (b.LLCHN) groups had a fully adjusted 8.85-, 7.88-, and 5.97-fold increased risk of mild and moderate liver dysfunction after being hospitalized of 3, 6, and 9 days compared to the baseline LR > 26.1 and NR < 62.0 (b.normal) groups. Severe liver dysfunction only presents significant differences after being adjusted for age, sex, and BMI. Consistently, Kaplan-Meier analyses showed that b.LLCHN reflects a better predictive value for different subsequent magnitude liver dysfunctions after admission of 3 and 6 days. To improve liver function in patients with preexisting AST ≥35 U/L, future management strategies should pay more attention to baseline LR ≤ 26.1 and NR ≥ 62.0 patients.
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Affiliation(s)
- Fang Liu
- Institute of Hepatology and Epidemiology, Affiliated Hangzhou Xixi Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Hong Liu
- Department of Pathology, Affiliated Hangzhou Xixi Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Wen-Yan Yu
- Medical Laboratory, Affiliated Hangzhou Xixi Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Zhan Liu
- Department of Anesthesiology, Affiliated Hangzhou Xixi Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Xia Zhang
- Medical Laboratory, Affiliated Hangzhou Xixi Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Yi Wang
- Institute of Hepatology and Epidemiology, Affiliated Hangzhou Xixi Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Liang-Bin Miao
- Institute of Hepatology and Epidemiology, Affiliated Hangzhou Xixi Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Zhao-Yi Li
- Institute of Hepatology and Epidemiology, Affiliated Hangzhou Xixi Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Jin-Song Huang
- Department of Hepatology, Affiliated Hangzhou Xixi Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Jian-Feng Bao
- Department of Hepatology, Affiliated Hangzhou Xixi Hospital, Zhejiang University School of Medicine, Hangzhou, China
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21
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A review of cardiovascular involvements associated with medications used to treat COVID-19 infection. COR ET VASA 2021. [DOI: 10.33678/cor.2020.073] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
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22
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Chen ZR, Liu J, Liao ZG, Zhou J, Peng HW, Gong F, Hu JF, Zhou Y. COVID-19 and gastroenteric manifestations. World J Clin Cases 2021; 9:4990-4997. [PMID: 34307549 PMCID: PMC8283602 DOI: 10.12998/wjcc.v9.i19.4990] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/26/2021] [Revised: 03/14/2021] [Accepted: 05/15/2021] [Indexed: 02/06/2023] Open
Abstract
Coronavirus disease 2019 (COVID-19), caused by the infection of a novel coronavirus [severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)], has become a pandemic. The infection has resulted in about one hundred million COVID-19 cases and millions of deaths. Although SARS-CoV-2 mainly spreads through the air and impairs the function of the respiratory system, it also attacks the gastrointestinal epithelial cells through the same receptor, angiotensin converting enzyme 2 receptor, which results in gastroenteric symptoms and potential fecal-oral transmission. Besides the infection of SARS-CoV-2, the treatments of COVID-19 also contribute to the gastroenteric manifestations due to the adverse drug reactions of anti-COVID-19 drugs. In this review, we update the clinical features, basic studies, and clinical practices of COVID-19-associated gastroenteric manifestations.
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Affiliation(s)
- Zhang-Ren Chen
- Department of Pharmacy, The First Affiliated Hospital of Nanchang University, Nanchang 330100, Jiangxi Province, China
| | - Jing Liu
- Department of Pharmacy, The First Affiliated Hospital of Nanchang University, Nanchang 330100, Jiangxi Province, China
| | - Zhi-Guo Liao
- Department of Pharmacy, The First Affiliated Hospital of Nanchang University, Nanchang 330100, Jiangxi Province, China
| | - Jian Zhou
- Department of Pharmacy, The First Affiliated Hospital of Nanchang University, Nanchang 330100, Jiangxi Province, China
| | - Hong-Wei Peng
- Department of Pharmacy, The First Affiliated Hospital of Nanchang University, Nanchang 330100, Jiangxi Province, China
| | - Fei Gong
- Department of Pharmacy, The First Affiliated Hospital of Nanchang University, Nanchang 330100, Jiangxi Province, China
| | - Jin-Fang Hu
- Department of Pharmacy, The First Affiliated Hospital of Nanchang University, Nanchang 330100, Jiangxi Province, China
| | - Ying Zhou
- Department of Pharmacy, The First Affiliated Hospital of Nanchang University, Nanchang 330100, Jiangxi Province, China
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23
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Arrieta A, Galvis AE, Morphew T, Ehwerhemuepha L, Osborne S, Enriquez C, Imfeld K, Hoang J, Nieves D, Ashouri N, Singh J, Nugent D. Safety and Antibody Kinetics of COVID-19 Convalescent Plasma for the Treatment of Moderate to Severe Cases of SARS-CoV-2 Infection in Pediatric Patients. Pediatr Infect Dis J 2021; 40:606-611. [PMID: 33967228 DOI: 10.1097/inf.0000000000003166] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
BACKGROUND Therapies against severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) and its life-threatening respiratory infection coronavirus disease 2019 (COVID-19) have been evaluated, including COVID-19 convalescent plasma (CCP). Multiple large reports of CCP treatment in adults exist. Pediatric data on CCP safety and efficacy are limited. METHODS Single-center prospective, open-label trial looking at safety, antibody kinetics and outcomes of CCP (10 mL/kg, max 1 unit) treatment for COVID-19 in hospitalized pediatric patients with moderate to severe disease or at high-risk for serious illness. RESULTS Thirteen patients were enrolled. No infusion-related adverse events occurred. No hematologic or metabolic adverse events were noted during hospitalization or at 3-weeks. Ten patients had clinical improvement by day 7 (WHO eight-category ordinal severity scale for COVID-19). Following CCP, anti-SARS-CoV-2 anti-nucleocapsid IgG increased significantly at 24 hours and high levels were sustained at 7- and 21-days. Transient IgM response was noted. Twelve patients (92.3%) were discharged home, 9 (75%) by day 7 post-CCP. One remained on invasive ventilatory support 42 days after CCP and was eventually discharged to an intermediate care facility. The single patient death was retrospectively confirmed to have had brain death before CCP. CONCLUSION CCP was well tolerated in pediatric patients, resulted in rapid antibody increase, and did not appear to interfere with immune responses measured at 21 days. More pediatric data are necessary to establish the efficacy of CCP, but our data suggest benefit in moderate to severe COVID-19 when used early. Other immunologic or antiviral interventions may be added as supported by emerging data.
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Affiliation(s)
- Antonio Arrieta
- From the CHOC Children's Hospital, Division of Infectious Diseases, Orange, California
- Department of Pediatrics, University of California, Irvine, California
| | - Alvaro E Galvis
- From the CHOC Children's Hospital, Division of Infectious Diseases, Orange, California
- Department of Pediatrics, University of California, Irvine, California
| | - Tricia Morphew
- CHOC Children's Hospital, Orange, California; Morphew Consulting, LLC
| | | | - Stephanie Osborne
- CHOC Children's Hospital of Orange County, Research Administration, Orange, California
| | - Claudia Enriquez
- CHOC Children's Hospital of Orange County, Research Administration, Orange, California
| | - Karen Imfeld
- CHOC Children's Hospital, Division of Hematology, Orange, California
| | - Janet Hoang
- CHOC Children's Hospital, Division of Hematology, Orange, California
| | - Delma Nieves
- From the CHOC Children's Hospital, Division of Infectious Diseases, Orange, California
- Department of Pediatrics, University of California, Irvine, California
| | - Negar Ashouri
- From the CHOC Children's Hospital, Division of Infectious Diseases, Orange, California
- Department of Pediatrics, University of California, Irvine, California
| | - Jasjit Singh
- From the CHOC Children's Hospital, Division of Infectious Diseases, Orange, California
- Department of Pediatrics, University of California, Irvine, California
| | - Diane Nugent
- Department of Pediatrics, University of California, Irvine, California
- CHOC Children's Hospital, Division of Hematology, Orange, California
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24
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Lam C, Siefkas A, Zelin NS, Barnes G, Dellinger RP, Vincent JL, Braden G, Burdick H, Hoffman J, Calvert J, Mao Q, Das R. Machine Learning as a Precision-Medicine Approach to Prescribing COVID-19 Pharmacotherapy with Remdesivir or Corticosteroids. Clin Ther 2021; 43:871-885. [PMID: 33865643 PMCID: PMC8006198 DOI: 10.1016/j.clinthera.2021.03.016] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2021] [Revised: 03/01/2021] [Accepted: 03/21/2021] [Indexed: 12/15/2022]
Abstract
PURPOSE Coronavirus disease-2019 (COVID-19) continues to be a global threat and remains a significant cause of hospitalizations. Recent clinical guidelines have supported the use of corticosteroids or remdesivir in the treatment of COVID-19. However, uncertainty remains about which patients are most likely to benefit from treatment with either drug; such knowledge is crucial for avoiding preventable adverse effects, minimizing costs, and effectively allocating resources. This study presents a machine-learning system with the capacity to identify patients in whom treatment with a corticosteroid or remdesivir is associated with improved survival time. METHODS Gradient-boosted decision-tree models used for predicting treatment benefit were trained and tested on data from electronic health records dated between December 18, 2019, and October 18, 2020, from adult patients (age ≥18 years) with COVID-19 in 10 US hospitals. Models were evaluated for performance in identifying patients with longer survival times when treated with a corticosteroid versus remdesivir. Fine and Gray proportional-hazards models were used for identifying significant findings in treated and nontreated patients, in a subset of patients who received supplemental oxygen, and in patients identified by the algorithm. Inverse probability-of-treatment weights were used to adjust for confounding. Models were trained and tested separately for each treatment. FINDINGS Data from 2364 patients were included, with men comprising slightly more than 50% of the sample; 893 patients were treated with remdesivir, and 1471 were treated with a corticosteroid. After adjustment for confounding, neither corticosteroids nor remdesivir use was associated with increased survival time in the overall population or in the subpopulation that received supplemental oxygen. However, in the populations identified by the algorithms, both corticosteroids and remdesivir were significantly associated with an increase in survival time, with hazard ratios of 0.56 and 0.40, respectively (both, P = 0.04). IMPLICATIONS Machine-learning methods have the capacity to identify hospitalized patients with COVID-19 in whom treatment with a corticosteroid or remdesivir is associated with an increase in survival time. These methods may help to improve patient outcomes and allocate resources during the COVID-19 crisis.
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Affiliation(s)
| | | | | | | | - R Phillip Dellinger
- Division of Critical Care Medicine, Cooper University Hospital/Cooper Medical School, Rowan University, Camden, New Jersey
| | - Jean-Louis Vincent
- Department of Intensive Care, Erasme University Hospital, Université Libre, Brussels, Belgium
| | - Gregory Braden
- Kidney Care and Transplant Associates of New England, Springfield, Massachusetts
| | - Hoyt Burdick
- Cabell Huntington Hospital, Huntington, West Virginia; School of Medicine, Marshall University, Huntington, West Virginia
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25
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Serag E, El-Zeftawy M. Environmental aspect and applications of nanotechnology to eliminate COVID-19 epidemiology risk. NANOTECHNOLOGY FOR ENVIRONMENTAL ENGINEERING 2021. [PMCID: PMC7917956 DOI: 10.1007/s41204-021-00108-1] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
Herein, we discuss fast development of the new coronavirus disease COVID-19, emerged in late 2019 in Wuhan, Hubei Province, China, the ground zero of the coronavirus pandemic, and associated with relatively high mortality rate. COVID-19 risk originates from its ability to transmit easily from person to person through the respiratory droplets released during sneezing, breathing, talking, singing, or coughing within a range of nearly 1.5–2 m. The review begins with an overview of COVID-19 origin and symptoms that range from common cold to severe respiratory illnesses and death. Then, it sheds light on the role of nanotechnology as an effective tool for fighting COVID-19 via contributions in diagnosis, treatment, and manufacture of protective equipment for people and healthcare workers. Emergency-approved therapeutics for clinical trial and prospective vaccines are discussed. Additionally, the present work addresses the risk of severe acute respiratory syndrome coronavirus transmission via wastewater and means of wastewater treatment and disinfection via nanoscale materials. The review concludes with a brief assessment of the government's efforts and contemporary propositions to minimize COVID-19 hazard and spreading.
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Affiliation(s)
- Eman Serag
- Marine Pollution Department, Environmental Division, National Institute of Oceanography and Fisheries, Kayet Bey, Elanfoushy, Alexandria, Egypt
| | - Marwa El-Zeftawy
- Biochemistry Department, Faculty of Veterinary Medicine, New Valley University, El-Kharga, New Valley Egypt
- Biological Screening and Preclinical Trial Lab, Biochemistry Department, Faculty of Science, Alexandria University, Alexandria, Egypt
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26
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Ikonne EU, Ikpeazu VO, Ugbogu OC, Emmanuel O, Nwakuche IP, Iweala EJ, Ugbogu EA. A review on the clinical trials of repurposing therapeutic drugs, mechanisms and preventive measures against SARS-CoV-2. Drug Metab Pers Ther 2021; 36:dmdi-2020-0184. [PMID: 33818026 DOI: 10.1515/dmpt-2020-0184] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2020] [Accepted: 01/23/2021] [Indexed: 11/15/2022]
Abstract
Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is a highly transmittable pathogenic viral infection that causes a disease known as COVID-19. It is a pandemic and public health challenge ravaging the world today. Unfortunately, with the daily increase of infected individuals, there is no known drug approved for the treatment of COVID-19. However, there are therapeutic drugs with the potentials to inhibit endocytic pathways, suppress ribonucleic acid (RNA) polymerase activities, and reduce the replication of SARS-CoV-2. These drugs modifications are aimed at reducing inflammation, time of recovery, and number of deaths. This review is aimed at providing updated information on the clinical manifestations, diagnosis, preventive measures and therapeutic drugs used against SARS-CoV-2. The finding of this review revealed that some of these drugs are transmembrane protease, serine 2, and angiotensin-converting enzyme 2 inhibitors with the capacity to block the entrance/replication of SARS-CoV-2 in a host cell and therefore, may be promising in preventing the spread and mortality of SARS-CoV-2. However, these drugs may cause detrimental health effects such as toxic and non-efficacy issues. Therefore great caution should be employed by health professionals when prescribing these drugs to COVID-19 patients.
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Affiliation(s)
- Eleazer U Ikonne
- Department of Optometry, Faculty of Health Sciences, Abia State University, Uturu, Abia State, Nigeria
| | - Victor O Ikpeazu
- Department of Biochemistry, Abia State University, Uturu, Abia State, Nigeria
| | - Ositadinma C Ugbogu
- Department of Microbiology, Abia State University, Uturu, Abia State, Nigeria
| | - Okezie Emmanuel
- Department of Biochemistry, Abia State University, Uturu, Abia State, Nigeria
| | - Ikechukwu P Nwakuche
- Department of Optometry, Faculty of Allied Health Sciences, Bayero University Kano, Kano, Nigeria
| | - Emeka J Iweala
- Department of Biochemistry, Covenant University, Ota, Ogun State, Nigeria
| | - Eziuche A Ugbogu
- Department of Biochemistry, Abia State University, Uturu, Abia State, Nigeria
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27
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Chatterjee S. Remdesivir: Critical Clinical Appraisal for COVID 19 Treatment. Drug Res (Stuttg) 2021; 71:138-148. [PMID: 33124007 PMCID: PMC8043717 DOI: 10.1055/a-1288-4078] [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: 05/29/2020] [Accepted: 10/06/2020] [Indexed: 02/06/2023]
Abstract
Remdesivir is presently been considered as 'molecule of hope' to curb the menace of COVID19. Non-availability of any USFDA approved drug has led to several attempt of drug-repurposing and development of new therapeutic molecules. However, Remdesivir has been found to be effective against a broad range of virus including SARS, MERS and COVID 19 through in-vitro studies. Several clinical research attempt are presently being conducted showing promising result yet not conclusive. This review summarized all such clinical trials to critically appraise the usage of Remdesivir against COVID 19 along with the publications related to the results of the clinical studies. The present regulatory aspect i. e. Emergency Use Authorization (EYA) and information of molecule and plausible mechanism is also dealt.
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28
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Umar HI, Siraj B, Ajayi A, Jimoh TO, Chukwuemeka PO. Molecular docking studies of some selected gallic acid derivatives against five non-structural proteins of novel coronavirus. J Genet Eng Biotechnol 2021; 19:16. [PMID: 33492492 PMCID: PMC7829640 DOI: 10.1186/s43141-021-00120-7] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2020] [Accepted: 01/12/2021] [Indexed: 12/16/2022]
Abstract
BACKGROUND The World Health Organization has recently declared a new coronavirus disease (COVID-19) a pandemic and a global health emergency. The pressure to produce drugs and vaccines against the ongoing pandemic has resulted in the use of some drugs such as azithromycin, chloroquine (sulfate and phosphate), hydroxychloroquine, dexamethasone, favipiravir, remdesivir, ribavirin, ivermectin, and lopinavir/ritonavir. However, reports from some of the clinical trials with these drugs have proved detrimental on some COVID-19 infected patients with side effects more of which cardiomyopathy, cardiotoxicity, nephrotoxicity, macular retinopathy, and hepatotoxicity have been recently reported. Realizing the need for potent and harmless therapeutic compounds to combat COVID-19, we attempted in this study to find promising therapeutic compounds against the imminent threat of this virus. In this current study, 16 derivatives of gallic acid were docked against five selected non-structural proteins of SARS-COV-2 known to be a good target for finding small molecule inhibitors against the virus, namely, nsp3, nsp5, nsp12, nsp13, and nsp14. All the protein crystal structures and 3D structures of the small molecules (16 gallic acid derivatives and 3 control drugs) were retrieved from the Protein database (PDB) and PubChem server respectively. The compounds with lower binding energy than the control drugs were selected and subjected to pharmacokinetics screening using AdmetSAR server. RESULTS 4-O-(6-galloylglucoside) gave binding energy values of - 8.4, - 6.8, - 8.9, - 9.1, and - 7.5 kcal/mol against Mpro, nsp3, nsp12, nsp13, and nsp15 respectively. Based on the ADMET profile, 4-O-(6-galloylglucoside) was found to be metabolized by the liver and has a very high plasma protein binding. CONCLUSION The result of this study revealed that 4-O-(6-galloylglucoside) could be a promising inhibitor against these SAR-Cov-2 proteins. However, there is still a need for further molecular dynamic simulation, in vivo and in vitro studies to support these findings.
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Affiliation(s)
- Haruna Isiyaku Umar
- Department of Biochemistry, School of Sciences, Federal University of Technology, Along Owo-Ilesha Express Way, P.M.B. 704, Akure, Ondo State Nigeria
- Ioncure Tech Pvt. Ltd., Delhi, 110085 India
| | - Bushra Siraj
- Ioncure Tech Pvt. Ltd., Delhi, 110085 India
- Dr. Zafar H. Zaidi Center for Proteomics, University of Karachi, Karachi, Pakistan
| | - Adeola Ajayi
- Department of Biochemistry, School of Sciences, Federal University of Technology, Along Owo-Ilesha Express Way, P.M.B. 704, Akure, Ondo State Nigeria
| | - Tajudeen O. Jimoh
- Faculty of Pharmaceutical Sciences, Department of Pharmacognosy and Pharmaceutical Botany, Chulalongkorn University, Bangkok, Thailand
- Department of Biochemistry, Habib Medical School, Islamic University in Uganda, P. O. Box 7689, Kampala, Uganda
| | - Prosper Obed Chukwuemeka
- Department of Biotechnology, School of sciences, Federal University of Technology, Akure, Ondo State Nigeria
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29
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Trougakos IP, Stamatelopoulos K, Terpos E, Tsitsilonis OE, Aivalioti E, Paraskevis D, Kastritis E, Pavlakis GN, Dimopoulos MA. Insights to SARS-CoV-2 life cycle, pathophysiology, and rationalized treatments that target COVID-19 clinical complications. J Biomed Sci 2021; 28:9. [PMID: 33435929 PMCID: PMC7801873 DOI: 10.1186/s12929-020-00703-5] [Citation(s) in RCA: 141] [Impact Index Per Article: 35.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2020] [Accepted: 12/23/2020] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND Gaining further insights into SARS-CoV-2 routes of infection and the underlying pathobiology of COVID-19 will support the design of rational treatments targeting the life cycle of the virus and/or the adverse effects (e.g., multi-organ collapse) that are triggered by COVID-19-mediated adult respiratory distress syndrome (ARDS) and/or other pathologies. MAIN BODY COVID-19 is a two-phase disease being marked by (phase 1) increased virus transmission and infection rates due to the wide expression of the main infection-related ACE2, TMPRSS2 and CTSB/L human genes in tissues of the respiratory and gastrointestinal tract, as well as by (phase 2) host- and probably sex- and/or age-specific uncontrolled inflammatory immune responses which drive hyper-cytokinemia, aggressive inflammation and (due to broad organotropism of SARS-CoV-2) collateral tissue damage and systemic failure likely because of imbalanced ACE/ANGII/AT1R and ACE2/ANG(1-7)/MASR axes signaling. CONCLUSION Here we discuss SARS-CoV-2 life cycle and a number of approaches aiming to suppress viral infection rates or propagation; increase virus antigen presentation in order to activate a robust and durable adaptive immune response from the host, and/or mitigate the ARDS-related "cytokine storm" and collateral tissue damage that triggers the severe life-threatening complications of COVID-19.
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Affiliation(s)
- Ioannis P Trougakos
- Department of Cell Biology and Biophysics, Faculty of Biology, National and Kapodistrian University of Athens, 15784, Athens, Greece.
| | - Kimon Stamatelopoulos
- Department of Clinical Therapeutics, School of Medicine, National and Kapodistrian University of Athens, 11528, Athens, Greece
| | - Evangelos Terpos
- Department of Clinical Therapeutics, School of Medicine, National and Kapodistrian University of Athens, 11528, Athens, Greece
| | - Ourania E Tsitsilonis
- Department of Animal and Human Physiology, Faculty of Biology, National and Kapodistrian University of Athens, 15784, Athens, Greece
| | - Evmorfia Aivalioti
- Department of Clinical Therapeutics, School of Medicine, National and Kapodistrian University of Athens, 11528, Athens, Greece
| | - Dimitrios Paraskevis
- Department of Hygiene, Epidemiology and Medical Statistics, School of Medicine, National and Kapodistrian University of Athens, 11527, Athens, Greece
| | - Efstathios Kastritis
- Department of Clinical Therapeutics, School of Medicine, National and Kapodistrian University of Athens, 11528, Athens, Greece
| | - George N Pavlakis
- Human Retrovirus Section, National Cancer Institute, Frederick, MD, 21702, USA
| | - Meletios A Dimopoulos
- Department of Clinical Therapeutics, School of Medicine, National and Kapodistrian University of Athens, 11528, Athens, Greece.
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30
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Hosseini Z, Ghodsi S, Hejazi SF. Persistent Complete Heart Block in a Patient with COVID-19 Infection: a Case Report. ACTA ACUST UNITED AC 2021; 3:259-262. [PMID: 33432301 PMCID: PMC7787236 DOI: 10.1007/s42399-020-00712-3] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/10/2020] [Indexed: 12/19/2022]
Abstract
The pandemic of COVID-19 as a global concern has emerged the need for data aggregation about various clinical pictures particularly cardiovascular complications. Although the incidence of advanced atrioventricular block (AVB) in these patients is not well established, few cases have been reported. We have reported a 48-year-old man with COVID-19 infection who presented with prodromal symptoms for 5 days preceding complete AVB found at the emergency department. Pulmonary involvement and PCR confirmed the diagnosis. The block persisted after recovery of the patient for more than 1 month. Pathophysiology of advanced AVB following COVID-19 infection is not well understood. Several factors including inflammatory response, immune system over activity, myocarditis, and medications have been underlined. Although conservative management may lead to spontaneous recovery of AVB, pacemaker implantation is reasonable in case of persistent conduction defect.
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Affiliation(s)
- Zahra Hosseini
- Department of Cardiology, Shahid Beheshti Hospital, Qom University of Medical Sciences, Qom, Iran
| | - Saeed Ghodsi
- Department of Cardiology, Shahid Beheshti Hospital, Qom University of Medical Sciences, Qom, Iran.,Research Department, Tehran Heart Center, Tehran University of Medical Sciences, North Kargar Street, Tehran, 14111713138 Iran
| | - Seyed Fakhreddin Hejazi
- Department of Cardiology, Shahid Beheshti Hospital, Qom University of Medical Sciences, Qom, Iran
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31
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Kivrak A, Ulaş B, Kivrak H. A comparative analysis for anti-viral drugs: Their efficiency against SARS-CoV-2. Int Immunopharmacol 2021; 90:107232. [PMID: 33290969 PMCID: PMC7703546 DOI: 10.1016/j.intimp.2020.107232] [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: 10/26/2020] [Revised: 11/20/2020] [Accepted: 11/20/2020] [Indexed: 12/27/2022]
Abstract
Coronavirus, known as the coronavirus pandemic, is continuing its spread across the world, with over 42 million confirmed cases in 189 countries and more than 1.15 million deaths. Although, scientists focus on the finding novel drugs and vaccine for SARS-CoV-2, there is no certain treatment for it. Antiviral drugs such as; oseltamivir, favipiravir, umifenovir, lopinavir, remdesivir, hydroxychloroquine, chloroquine, azithromycin, ascorbic acid, corticosteroids, are mostly used for patients. They prevent cytokine storm that is the main reason of deaths related to SARS-CoV-2. In addition, anti-inflammatory agents have critical roles to inhibit the lung injury and multisystem organ dysfunction. The combination with anti-viral drugs with other drugs displays high synergistic effects. In the present study, the drugs used for Covid-19 are analyzed and compare the efficiency for the Covid-19 patients from the different continents including USA, South Korea, Italy, Spain, Germany, Russia, Brazil, Turkey, and China. Nowadays, all countries tried to find vaccine and new drug candidates for SARS-CoV-2, but anti-viral drugs may be the best candidates for the treatment of Covid-19 before finding novel anti-Covid drug.
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Affiliation(s)
- Arif Kivrak
- Department of Chemistry, Faculty of Sciences, Van Yuzuncu Yil University, 65000 Van, Turkey.
| | - Berdan Ulaş
- Department of Chemical Engineering, Faculty of Engineering, Van Yuzuncu Yil University, 65000 Van, Turkey
| | - Hilal Kivrak
- Department of Chemical Engineering, Faculty of Engineering, Van Yuzuncu Yil University, 65000 Van, Turkey
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32
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Wu Q, Fan X, Hong H, Gu Y, Liu Z, Fang S, Wang Q, Cai C, Fang J. Comprehensive assessment of side effects in COVID-19 drug pipeline from a network perspective. Food Chem Toxicol 2020; 145:111767. [PMID: 32971210 PMCID: PMC7505223 DOI: 10.1016/j.fct.2020.111767] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2020] [Revised: 09/09/2020] [Accepted: 09/17/2020] [Indexed: 12/21/2022]
Abstract
Currently, coronavirus disease 2019 (COVID-19), has posed an imminent threat to global public health. Although some current therapeutic agents have showed potential prevention or treatment, a growing number of associated adverse events have occurred on patients with COVID-19 in the course of medical treatment. Therefore, a comprehensive assessment of the safety profile of therapeutic agents against COVID-19 is urgently needed. In this study, we proposed a network-based framework to identify the potential side effects of current COVID-19 drugs in clinical trials. We established the associations between 116 COVID-19 drugs and 30 kinds of human tissues based on network proximity and gene-set enrichment analysis (GSEA) approaches. Additionally, we focused on four types of drug-induced toxicities targeting four tissues, including hepatotoxicity, renal toxicity, lung toxicity, and neurotoxicity, and validated our network-based predictions by preclinical and clinical evidence available. Finally, we further performed pharmacovigilance analysis to validate several drug-tissue toxicities via data mining adverse event reporting data, and we identified several new drug-induced side effects without labeling in Food and Drug Administration (FDA) drug instructions. Overall, this study provides forceful approaches to assess potential side effects on COVID-19 drugs, which will be helpful for their safe use in clinical practice and promoting the discovery of antiviral therapeutics against SARS-CoV-2.
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Affiliation(s)
- Qihui Wu
- Clinical Research Center, Hainan Provincial Hospital of Traditional Chinese Medicine, Guangzhou University of Chinese Medicine, Haikou, China; Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, China.
| | - Xiude Fan
- Lerner Research Institute, Cleveland Clinic, Cleveland, USA.
| | - Honghai Hong
- Department of Clinical Laboratory, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.
| | - Yong Gu
- Clinical Research Center, Hainan Provincial Hospital of Traditional Chinese Medicine, Guangzhou University of Chinese Medicine, Haikou, China.
| | - Zhihong Liu
- Guangdong Institute of Microbiology, Guangdong Academy of Sciences, Guangzhou, China.
| | - Shuhuan Fang
- Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, China.
| | - Qi Wang
- Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, China.
| | - Chuipu Cai
- Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, China.
| | - Jiansong Fang
- Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, China; Lerner Research Institute, Cleveland Clinic, Cleveland, USA.
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Moradi F, Enjezab B, Ghadiri-Anari A. The role of androgens in COVID-19. Diabetes Metab Syndr 2020; 14:2003-2006. [PMID: 33091758 PMCID: PMC7557269 DOI: 10.1016/j.dsx.2020.10.014] [Citation(s) in RCA: 34] [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: 10/07/2020] [Revised: 10/11/2020] [Accepted: 10/13/2020] [Indexed: 01/08/2023]
Abstract
BACKGROUND AND AIM The coronavirus disease 2019 (COVID-19) pandemic is a global health emergency. According to the findings, male patients with COVID-19 infection are at an increased risk for severe complications than females. The causes of this issue are unknown and are most probably multifactorial. Sexual hormones affect the immune system, so estrogen strengthens the immune system, and testosterone suppresses it. Due to the reports of the high prevalence of androgenic alopecia in hospitalized patients with COVID-19 and a higher risk of respiratory disease and increased use of allergy/asthma medications among patients with polycystic ovary syndrome (PCOS) as a hyperandrogenism condition compared with non-PCOS women, this review aimed to evaluate androgens role in COVID-19. METHODS 42 related articles from 2008 to 2020 were reviewed with the keywords of androgens, hormonal factors, and hair loss in combination with COVID-19 in medical research databases. RESULTS The evidence of transmembrane protease, serine 2 (TMPRSS2) expression in lung tissue, which is an androgen-regulated gene and expressed mainly in the adult prostate may interpret the increased susceptibility of the male gender to severe COVID-19 complications. Moreover, angiotensin-converting enzyme 2 (ACE-2) acts as a functional receptor for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and male hormones are effective in the ACE-2 passageway and simplify SARS-CoV-2 entry into host cells. CONCLUSION Further studies on the severity of symptoms in patients with COVID-19 in other hyperandrogenism conditions compared to the control group are recommended.
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Affiliation(s)
| | - Behnaz Enjezab
- Research Center for Nursing and Midwifery Care, Department of Midwifery, Faculty of Nursing and Midwifery, Shahid Sadoughi University of Medical Sciences, Yazd, Iran.
| | - Akram Ghadiri-Anari
- Department of Internal Medicine, Diabetes Research Center, Shahid Sadoughi University of Medical Sciences, Yazd, Iran.
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34
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Gupta AK, Parker BM, Priyadarshi V, Parker J. Cardiac Adverse Events With Remdesivir in COVID-19 Infection. Cureus 2020; 12:e11132. [PMID: 33240723 PMCID: PMC7682945 DOI: 10.7759/cureus.11132] [Citation(s) in RCA: 44] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Since December 2019, coronavirus has gradually progressed to a pandemic with no efficacious treatment. Remdesivir is an antiviral medication and inhibitor of viral RNA dependent RNA polymerase with inhibitory action against SARS-CoV virus. Two patients diagnosed with coronavirus infection with worsening respiratory status were initiated with multimodality therapy with antibiotics, steroids and remdesivir. After initiation of remdesivir, the patients' developed bradycardia, with one of the two also showing signs of worsening QT interval. This reverted upon stopping remdesvir therapy. The prevalence of bradycardia with prolonged QT interval is not well-known yet with this medication.
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Affiliation(s)
| | | | | | - John Parker
- Obstetrics and Gynaecology, AdventHealth Altamonte, Altamonte Springs, USA
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35
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Keretsu S, Bhujbal SP, Cho SJ. Rational approach toward COVID-19 main protease inhibitors via molecular docking, molecular dynamics simulation and free energy calculation. Sci Rep 2020; 10:17716. [PMID: 33077821 PMCID: PMC7572583 DOI: 10.1038/s41598-020-74468-0] [Citation(s) in RCA: 82] [Impact Index Per Article: 16.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2020] [Accepted: 09/28/2020] [Indexed: 02/07/2023] Open
Abstract
In the rapidly evolving coronavirus disease (COVID-19) pandemic, repurposing existing drugs and evaluating commercially available inhibitors against druggable targets of the virus could be an effective strategy to accelerate the drug discovery process. The 3C-Like proteinase (3CLpro) of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been identified as an important drug target due to its role in viral replication. The lack of a potent 3CLpro inhibitor and the availability of the X-ray crystal structure of 3CLpro (PDB-ID 6LU7) motivated us to perform computational studies to identify commercially available potential inhibitors. A combination of modeling studies was performed to identify potential 3CLpro inhibitors from the protease inhibitor database MEROPS ( https://www.ebi.ac.uk/merops/index.shtml ). Binding energy evaluation identified key residues for inhibitor design. We found 15 potential 3CLpro inhibitors with higher binding affinity than that of an α-ketoamide inhibitor determined via X-ray structure. Among them, saquinavir and three other investigational drugs aclarubicin, TMC-310911, and faldaprevir could be suggested as potential 3CLpro inhibitors. We recommend further experimental investigation of these compounds.
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Affiliation(s)
- Seketoulie Keretsu
- Department of Biomedical Sciences, College of Medicine, Chosun University, Gwangju, 501-759, Republic of Korea
| | - Swapnil P Bhujbal
- Department of Biomedical Sciences, College of Medicine, Chosun University, Gwangju, 501-759, Republic of Korea
| | - Seung Joo Cho
- Department of Biomedical Sciences, College of Medicine, Chosun University, Gwangju, 501-759, Republic of Korea.
- Department of Cellular Molecular Medicine, College of Medicine, Chosun University, 375 Seosuk-dong, Dong-gu, Gwangju, 501-759, Republic of Korea.
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36
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Skalny AV, Lima TRR, Ke T, Zhou JC, Bornhorst J, Alekseenko SI, Aaseth J, Anesti O, Sarigiannis DA, Tsatsakis A, Aschner M, Tinkov AA. Toxic metal exposure as a possible risk factor for COVID-19 and other respiratory infectious diseases. Food Chem Toxicol 2020; 146:111809. [PMID: 33069759 PMCID: PMC7563920 DOI: 10.1016/j.fct.2020.111809] [Citation(s) in RCA: 54] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2020] [Revised: 09/25/2020] [Accepted: 10/01/2020] [Indexed: 01/08/2023]
Abstract
Multiple medical, lifestyle, and environmental conditions, including smoking and particulate pollution, have been considered as risk factors for COronaVIrus Disease 2019 (COVID-19) susceptibility and severity. Taking into account the high level of toxic metals in both particulate matter (PM2.5) and tobacco smoke, the objective of this review is to discuss recent data on the role of heavy metal exposure in development of respiratory dysfunction, immunotoxicity, and severity of viral diseases in epidemiological and experimental studies, as to demonstrate the potential crossroads between heavy metal exposure and COVID-19 severity risk. The existing data demonstrate that As, Cd, Hg, and Pb exposure is associated with respiratory dysfunction and respiratory diseases (COPD, bronchitis). These observations corroborate laboratory findings on the role of heavy metal exposure in impaired mucociliary clearance, reduced barrier function, airway inflammation, oxidative stress, and apoptosis. The association between heavy metal exposure and severity of viral diseases, including influenza and respiratory syncytial virus has been also demonstrated. The latter may be considered a consequence of adverse effects of metal exposure on adaptive immunity. Therefore, reduction of toxic metal exposure may be considered as a potential tool for reducing susceptibility and severity of viral diseases affecting the respiratory system, including COVID-19.
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Affiliation(s)
- Anatoly V Skalny
- IM Sechenov First Moscow State Medical University (Sechenov University), Moscow, Russia; Federal Research Centre of Biological Systems and Agro-technologies of the Russian Academy of Sciences, Orenburg, Russia.
| | - Thania Rios Rossi Lima
- São Paulo State University - UNESP, Center for Evaluation of Environmental Impact on Human Health (TOXICAM), Botucatu, SP, Brazil; Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, NY, USA
| | - Tao Ke
- Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, NY, USA
| | - Ji-Chang Zhou
- School of Public Health (Shenzhen), Sun Yat-sen University, Shenzhen, Guangdong Province, China
| | - Julia Bornhorst
- Food Chemistry, Faculty of Mathematics and Natural Sciences, University of Wuppertal, Wuppertal, Germany
| | - Svetlana I Alekseenko
- I.I. Mechnikov North-Western State Medical University, St. Petersburg, Russia; K.A. Rauhfus Children's City Multidisciplinary Clinical Center for High Medical Technologies, St. Petersburg, Russia
| | - Jan Aaseth
- IM Sechenov First Moscow State Medical University (Sechenov University), Moscow, Russia; Research Department, Innlandet Hospital Trust, Brumunddal, Norway
| | - Ourania Anesti
- Laboratory of Toxicology, Medical School, University of Crete, Voutes, Heraklion, Crete, Greece; HERACLES Research Center on the Exposome and Health, Center for Interdisciplinary Research and Innovation, Aristotle University of Thessaloniki, Thermi, Greece
| | - Dimosthenis A Sarigiannis
- HERACLES Research Center on the Exposome and Health, Center for Interdisciplinary Research and Innovation, Aristotle University of Thessaloniki, Thermi, Greece; University School of Advanced Studies IUSS, Pavia, Italy
| | - Aristides Tsatsakis
- IM Sechenov First Moscow State Medical University (Sechenov University), Moscow, Russia; Laboratory of Toxicology, Medical School, University of Crete, Voutes, Heraklion, Crete, Greece
| | - Michael Aschner
- IM Sechenov First Moscow State Medical University (Sechenov University), Moscow, Russia; Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, NY, USA
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