#Ribavirin, #Remdesivir, #Sofosbuvir, #Galidesivir, and #Tenofovir Against #SARS-CoV-2 RNA Dependent RNA Polymerase (RdRp): A Molecular Docking Study (Life Sci., abstract)

[Source: US National Library of Medicine, full page: (LINK). Abstract, edited.]

Life Sci, 117592 2020 Mar 25 [Online ahead of print]

Ribavirin, Remdesivir, Sofosbuvir, Galidesivir, and Tenofovir Against SARS-CoV-2 RNA Dependent RNA Polymerase (RdRp): A Molecular Docking Study

Abdo A Elfiky 1

Affiliation: 1 Biophysics Department, Faculty of Sciences, Cairo University, Giza, Egypt. Electronic address: abdo@sci.cu.edu.eg.

PMID: 32222463 DOI: 10.1016/j.lfs.2020.117592

 

Abstract

Aims:

A new human coronavirus (HCoV), which has been designated SARS-CoV-2, began spreading in December 2019 in Wuhan City, China causing pneumonia called COVID-19. The spread of SARS-CoV-2 has been faster than any other coronaviruses that have succeeded in crossing the animal-human barrier. There is concern that this new virus will spread around the world as did the previous two HCoVs-Severe Acute Respiratory Syndrome (SARS) and Middle East Respiratory Syndrome (MERS)-each of which caused approximately 800 deaths in the years 2002 and 2012, respectively. Thus far, 11,268 deaths have been reported from the 258,842 confirmed infections in 168 countries.

Main methods:

In this study, the RNA-dependent RNA polymerase (RdRp) of the newly emerged coronavirus is modeled, validated, and then targeted using different anti-polymerase drugs currently on the market that have been approved for use against various viruses.

Key findings:

The results suggest the effectiveness of Ribavirin, Remdesivir, Sofosbuvir, Galidesivir, and Tenofovir as potent drugs against SARS-CoV-2 since they tightly bind to its RdRp. In addition, the results suggest guanosine derivative (IDX-184), Setrobuvir, and YAK as top seeds for antiviral treatments with high potential to fight the SARS-CoV-2 strain specifically.

Significance:

The availability of FDA-approved anti-RdRp drugs can help treat patients and reduce the danger of the mysterious new viral infection COVID-19. The drugs mentioned above can tightly bind to the RdRp of the SARS-CoV-2 strain and thus may be used to treat the disease. No toxicity measurements are required for these drugs since they were previously tested prior to their approval by the FDA.

Keywords: COVID-19; Drug repurposing; Molecular docking; RdRp; SARS-CoV-2; Structural bioinformatics.

Copyright © 2020. Published by Elsevier Inc.

Conflict of interest statement – Declaration of competing interest: The author declares that there is no competing interest in this work.

Keywords: SARS-CoV-2; COVID-19; Antivirals.

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Novel #coronavirus #treatment with #ribavirin: Groundwork for evaluation concerning #COVID19 (J Med Virol., abstract)

[Source: Journal of Medical Virology, full page: (LINK). Abstract, edited.]

Novel coronavirus treatment with ribavirin: Groundwork for evaluation concerning COVID‐19

Jahan S. Khalili,  Hai Zhu,  Amanda Mak,  Yongqi Yan,  Yi Zhu

First published: 30 March 2020 | DOI:  https://doi.org/10.1002/jmv.25798

This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version of Record. Please cite this article as doi: 10.1002/jmv.25798

 

Abstract

Confronting the challenge of the outbreak of COVID‐19 should sharpen our focus on global drug access as a key issue in anti‐viral therapy testing. The testing and adoption of effective therapies for novel coronaviruses is hampered by the challenge of conducting controlled studies during a state of emergency. The access to direct anti‐viral drugs such as ribavirin that have an existing inventory and reliable supply chain may be a priority consideration for therapies developed for the 2019‐nCoV infection outbreaks and any strain variants that may emerge. Based on the direct anti‐viral activity of ribavirin against 2019‐nCoV in vitro and evidence for potency enhancement strategies developed during the prior SARS and MERS outbreaks, ribavirin may significantly impact our ability to end the lingering outbreaks in China and slow outbreaks in other countries. The apparent COVID‐19 pandemic provides an opportunity to follow dosage guidelines for treatment with ribavirin, test new therapeutic concepts, and conduct controlled testing to apply the scientific rigor required to address the controversy around this mainstay of anti‐viral therapy.

This article is protected by copyright. All rights reserved.

Keywords: SARS-CoV-2; COVID-19; Antivirals; Ribavirin.

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The #Trial of #Chloroquine in the #Treatment of #Coronavirus Disease 2019 (#COVID19) and Its Research Progress in Forensic #Toxicology (Fa Yi Xue Za Zhi, abstract)

[Source: US National Library of Medicine, full page: (LINK). Abstract, edited.]

 Fa Yi Xue Za Zhi, 36 (2) 2020 Mar 25 [Online ahead of print]

The Trial of Chloroquine in the Treatment of Corona Virus Disease 2019 (COVID-19) and Its Research Progress in Forensic Toxicology

[Article in English, Chinese]

Y J Duan 1, Q Liu 1, S Q Zhao 1, F Huang 1, L Ren 1, L Liu 1, Y W Zhou 1

Affiliation: 1 Department of Forensic Medicine, Tongji Medical College, Huanzhong University of Science and Technology, Wuhan 430030, China.

PMID: 32212513 DOI: 10.12116/j.issn.1004-5619.2020.02.001

 

Abstract in English , Chinese

Chloroquine is a long-established prescription drug that is often used clinically to treat malaria and connective tissue diseases. Since December 2019, COVID-19 (corona virus disease 2019) outbreaks caused by SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) has occurred in China and many countries around the world. Due to the lack of drugs against COVID-19, the disease spreads rapidly and the mortality rate is relatively high. Therefore, specific drugs against SARS-CoV-2 need to be quickly screened. The antimalarial drug Chloroquine phosphate which has already been approved is confirmed to have an anti-SARS-CoV-2 effect and has been included in diagnostic and therapeutic guidelines. However, awareness of the risk of chloroquine phosphate causing acute poisoning or even death should be strengthened. The dosage used according to current clinical recommended dosage and course of treatment are larger than that of previous treatment of malaria. Many provinces have required close clinical monitoring of adverse reactions. This paper reviews the pharmacological effects, poisoning and toxicological mechanisms, in vivo metabolism and distribution, and forensic issues of chloroquine drugs, in order to provide help to forensic practice and clinical work.

Keywords: forensic pathology; forensic toxicology; chloroquine; corona virus disease 2019 (COVID-19); review.

Copyright© by the Editorial Department of Journal of Forensic Medicine.

Conflict of interest statement – The authors of this article and the planning committee members and staff have no relevant financial relationships with commercial interests to disclose.

Keywords: SARS-CoV-2; COVID-19; Antivirals; Chloroquine.

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#Influenza A and B viruses with reduced #baloxavir susceptibility display attenuated in vitro #fitness but retain ferret #transmissibility (Proc Natl Acad Sci USA, abstract)

[Source: Proceedings of the National Academy of Sciences of the United States of America, full page: (LINK). Abstract, edited.]

Influenza A and B viruses with reduced baloxavir susceptibility display attenuated in vitro fitness but retain ferret transmissibility

Jeremy C. Jones, Philippe Noriel Q. Pascua, Thomas P. Fabrizio, Bindumadhav M. Marathe, Patrick Seiler, Subrata Barman, Richard J. Webby, Robert G. Webster, and Elena A. Govorkova

PNAS first published March 26, 2020 | DOI: https://doi.org/10.1073/pnas.1916825117

Contributed by Robert G. Webster, February 12, 2020 (sent for review October 2, 2019; reviewed by Rodney S. Daniels and Lieve Naesens)

 

Significance

The emergence of influenza viruses with reduced susceptibility to baloxavir marboxil (BXM) would limit the clinical utility of this novel antiviral. To assess the risk of such resistance emerging, we evaluated influenza A and B viruses carrying BXM-reduced susceptibility substitutions and compared their fitness to that of their drug-susceptible wild-type (I38-WT) counterparts. The 38T/F/M substitutions inhibited activity of the virus PA protein, and two of them (38T/F) hindered virus replication in cells. Even so, 38T/F/M viruses could transmit between ferrets, the gold-standard model for human transmission. These findings argue that there is a risk of transmission of BXM-resistant viruses from treated individuals. Whether such viruses could compete with WT viruses in spreading through the wider untreated community is less clear.

 

Abstract

Baloxavir marboxil (BXM) was approved in 2018 for treating influenza A and B virus infections. It is a first-in-class inhibitor targeting the endonuclease activity of the virus polymerase acidic (PA) protein. Clinical trial data revealed that PA amino acid substitutions at residue 38 (I38T/F/M) reduced BXM potency and caused virus rebound in treated patients, although the fitness characteristics of the mutant viruses were not fully defined. To determine the fitness impact of the I38T/F/M substitutions, we generated recombinant A/California/04/2009 (H1N1)pdm09, A/Texas/71/2017 (H3N2), and B/Brisbane/60/2008 viruses with I38T/F/M and examined drug susceptibility in vitro, enzymatic properties, replication efficiency, and transmissibility in ferrets. Influenza viruses with I38T/F/M substitutions exhibited reduced baloxavir susceptibility, with 38T causing the greatest reduction. The I38T/F/M substitutions impaired PA endonuclease activity as compared to that of wild-type (I38-WT) PA. However, only 38T/F A(H3N2) substitutions had a negative effect on polymerase complex activity. The 38T/F substitutions decreased replication in cells among all viruses, whereas 38M had minimal impact. Despite variable fitness consequences in vitro, all 38T/M viruses disseminated to naive ferrets by contact and airborne transmission, while 38F-containing A(H3N2) and B viruses failed to transmit via the airborne route. Reversion of 38T/F/M to I38-WT was rare among influenza A viruses in this study, suggesting stable retention of 38T/F/M genotypes during these transmission events. BXM reduced susceptibility-associated mutations had variable effects on in vitro fitness of influenza A and B viruses, but the ability of these viruses to transmit in vivo indicates a risk of their spreading from BXM-treated individuals.

influenza – endonuclease inhibitor – baloxavir marboxil – PA protein – I38T substitution

 

Footnotes

1 To whom correspondence may be addressed. Email: Jeremy.jones@stjude.org or robert.webster@stjude.org.

Author contributions: J.C.J., P.N.Q.P., T.P.F., R.J.W., R.G.W., and E.A.G. designed research; J.C.J., P.N.Q.P., B.M.M., and P.S. performed research; J.C.J., P.N.Q.P., T.P.F., and S.B. contributed new reagents/analytic tools; J.C.J., P.N.Q.P., T.P.F., and E.A.G. analyzed data; and J.C.J., P.N.Q.P., R.J.W., R.G.W., and E.A.G. wrote the paper.

Reviewers: R.S.D., The Francis Crick Institute; and L.N., Katholieke Universiteit Leuven.

Competing interest statement: E.A.G. reports receiving consultant fees and travel support from Genentech/Roche for serving on an advisory board. The other authors declare no conflicts of interest.

This article contains supporting information online at https://www.pnas.org/lookup/suppl/doi:10.1073/pnas.1916825117/-/DCSupplemental.

Published under the PNAS license.

Keywords: Seasonal Influenza; Antivirals; Drugs Resistance; Baloxavir.

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#Controversial #treatments: an updated understanding of the #Coronavirus Disease 2019 (J Med Virol., abstract)

[Source: Journal of Medical Virology, full page: (LINK). Abstract, edited.]

Controversial treatments: an updated understanding of the Coronavirus Disease 2019

Cantong Zhang,  Shaoying Huang,  Fengping Zheng,  Yong Dai

First published: 26 March 2020 | DOI: https://doi.org/10.1002/jmv.25788

This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version of Record. Please cite this article as doi: 10.1002/jmv.25788

 

Abstract

An outbreak of severe acute respiratory syndrome‐related coronavirus 2 (SARS‐CoV‐2) infection has posed significant threats to international health and the economy. In the absence of specific treatment for this virus, there is an urgent need to learn from the experience and lessons in China. To reduce the case‐fatality rate among COVID‐19 patients, we should not ignore the complications, such as RNAaemia, acute respiratory distress syndrome, and multiple organ dysfunction. To help understand the advantages and limitations of differential treatments, we provide a timely review and discuss the complications and corresponding major treatments, especially controversial ones such as antiviral therapy (remdesivir, ribavirin, chloroquine), glucocorticoid therapy, extracorporeal support including an artificial liver system (ALS) and extracorporeal membrane oxygenation (ECMO), based on available evidence. As a result, we suggest that antiviral therapy and organ function support are vital to reduce mortality for mild patients and critical patients, respectively.

This article is protected by copyright. All rights reserved.

Keywords: SARS-CoV-2; COVID-19; Antivirals; ECMO.

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#Pharmacologic #Treatments and #Supportive Care for #MERS #Coronavirus (Emerg Infect Dis., abstract)

[Source: US Centers for Disease Control and Prevention (CDC), Emerging Infectious Diseases Journal, full page: (LINK). Abstract, edited.]

Pharmacologic Treatments and Supportive Care for Middle East Respiratory Syndrome

Taylor Kain, Patrick J. Lindsay, Neill K.J. Adhikari, Yaseen M. Arabi, Maria D. Van Kerkhove, and Robert A. Fowler

Author affiliations: University of Toronto, Toronto, Ontario, Canada (T. Kain, P.J. Lindsay, N.K.J. Adhikari, R.A. Fowler); Harvard University, Boston, Massachusetts, USA (P.J. Lindsay); Sunnybrook Health Sciences Center, Toronto (N.K.J. Adhikari, R.A. Fowler); King Saud Bin Abdulaziz University for Health Center, Riyadh, Saudi Arabia (Y.M. Arabi); King Abdullah International Medical Research Center, Riyadh (Y.M. Arabi); World Health Organization, Geneva, Switzerland (M.D. Van Kerkhove)

 

Abstract

Available animal and cell line models have suggested that specific therapeutics might be effective in treating Middle East respiratory syndrome (MERS). We conducted a systematic review of evidence for treatment with pharmacologic and supportive therapies. We developed a protocol and searched 5 databases for studies describing treatment of MERS and deaths in MERS patients. Risk of bias (RoB) was assessed by using ROBINS-I tool. We retrieved 3,660 unique citations; 20 observational studies met eligibility, and we studied 13 therapies. Most studies were at serious or critical RoB; no studies were at low RoB. One study, at moderate RoB, showed reduced mortality rates in severe MERS patients with extracorporeal membrane oxygenation; no other studies showed a significant lifesaving benefit to any treatment. The existing literature on treatments for MERS is observational and at moderate to critical RoB. Clinical trials are needed to guide treatment decisions.

Keywords: MERS-CoV; ECMO.

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