Is remdesivir the therapeutic answer for COVID-19: a review of current knowledge
Keywords:SARS-Cov-2, COVID-19, Remdesivir, RNA-dependent RNA polymerase
As the world races to find the solution to the COVID-19 pandemic, an investigational agent which has triggered worldwide interest is remdesivir. Though failing clinical trials for treatment of Ebola virus disease, remdesivir has shown efficacy in numerous viral studies involving SARS-CoV-2. Reports from compassionate use of remdesivir in hospitalized patients of COVID-19 have been promising. But the real picture about the safety and efficacy of remdesivir can only be known after completion of randomized clinical trials. In this review, we aim to highlight the salient features of pharmacokinetics and pharmacodynamics of remdesivir known so far and its plausible role in management of COVID-19. We searched the PubMed database and Google Scholar for published literature using the key words: remdesivir, human coronavirus, novel coronavirus, COVID-19, SARS-CoV 2, mechanism of action, pharmacokinetics, pharmacodynamics and compassionate use till 1st May 2020. The U. S. national library of medical trials registry was searched for ongoing trials with remdesivir among patients of COVID-19. Remdesivir is a prodrug of a nucleoside Analog that inhibits RNA replication by binding to viral RNA dependent RNA polymerase. It is being employed in many global phase-3 clinical trials for evaluating the efficacy and safety of the drug in patients of COVID-19.
Leonardi D, Polodori C, Polidori P. The healthcare and pharmaceutical vulnerability emerging from the new Coronavirus outbreak. Eur J Hosp Pharm. 2020;0:1-2.
Hui DS, Azhar IE, Madani TA, Ntoumi F, Kock R, Dar O. The continuing 2019-nCoV epidemic threat of novel coronaviruses to global health the latest 2019 novel coronavirus outbreak in Wuhan, China. Int J Infectious Diseases. 2020;91:264-6.
Wu Z, McGoogan JM. Characteristics of and Important Lessons from the Coronavirus Disease 2019 (COVID-19) Outbreak in China: Summary of a Report of 72 314 Cases from the Chinese Center for Disease Control and Prevention. JAMA. 2020;323(13):1239-42.
WHO Director-General’s opening remarks at the media briefing on COVID-19 - 3 March 2020 - World Health Organization, March 3, 2020.
World Health Organization. Coronavirus (COVID-19) Pandemic. Available at: https://www.who.int/emergencies/diseases/novel-coronavirus-2019.
Sheahan TP, Sims AC, Leist SR, Schafer A, Won J, Brown AJ, et al. Comparative therapeutic efficacy of remdesivir and combination lopinavir, ritonavir, and interferon beta against MERS-CoV. Nature Communications. 2020;11(1):1-4.
Chang YC, Tung YA, Lee KH, Chen TF, Hsiao YC, Chang HC, et al. Potential therapeutic agents for COVID-19 based on the analysis of protease and RNA polymerase docking.
Elfiky AA. Ribavirin, Remdesivir, Sofosbuvir, Galidesivir, and Tenofovir against SARS-CoV-2 RNA dependent RNA polymerase (RdRp): a molecular docking study. Life Sci. 2020;25:117592.
World Health Organization. “Solidarity” clinical trial for COVID-19 treatments. Available at: https://www.who.int/emergencies/diseases/novel-coronavirus-2019/global-research-on-novel-coronavirus-2019-ncov/solidarity-clinical-trial-for-covid-19-treatments.
Warren TK, Jordan R, Lo MK, Ray AS, Mackman RL, Soloveva V, et al. Therapeutic efficacy of the small molecule GS-5734 against Ebola virus in rhesus monkeys. Nature. 2016;531(7594):381-5.
Brown AJ, Won JJ, Graham RL, Dinnon KH, Sims AC, Feng JY, et al. Broad spectrum antiviral remdesivir inhibits human endemic and zoonotic delta coronaviruses with a highly divergent RNA dependent RNA polymerase. Antiviral Res. 2019;169:104541.
Warren TK, Siegel D, Hui HC, Doerffler E, Clarke MO, Chun K, et al. Discovery and Synthesis of GS-5734, a Phosphoramidate Prodrug of a Pyrrolo [2, 1 f][triazin 4 amino] Adenine C-Nucleoside (GS 5734) for the Treatment of Ebola and Emerging Viruses. USAMRIID Ft Detrick United States; 2017.
Lo MK, Jordan R, Arvey A, Sudhamsu J, Ranjan SP, Hotard AL, et al. GS-5734 and its parent nucleoside analog inhibit Filo, Pneumo, and Paramyxoviruses. Scientific Reports. 2017;7:43395.
Mulangu S, Dodd LE, Davey RT, Mbaya TO, Proschan M, Mukadi D, et al. A randomized, controlled trial of Ebola virus disease therapeutics. New England J Med. 2019;381(24):2293-303.
Holshue ML, Bolt DC, Lindquist S, Lofy KH, Wiesman J, Bruce H, et al. First case of 2019 novel coronavirus in the United States. New England J Med. 2020;382(19):1787-99.
Dijkman R, Jebbink MF, Gaunt E, Rossen JW, Templeton KE, Kuijpers TW, et al. The dominance of human coronavirus OC43 and NL63 infections in infants. J Clin Virology. 2012;53(2):135-9.
Falsey AR, Walsh EE, Hayden FG. Rhinovirus and coronavirus infection-associated hospitalizations among older adults. J Infectious Diseases. 2002;185(9):1338-41.
Wit DE, Doremalen VN, Falzarano D, Munster VJ. SARS and MERS: recent insights into emerging coronaviruses. Nature Reviews Microbiology. 2016;14(8):523.
Lai CC, Shih TP, Ko WC, Tang HJ, Hsueh PR. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and corona virus disease-2019 (COVID-19): the epidemic and the challenges. Int J Antimicrobial Agents. 2020:105924.
Elfiky AA, Mahdy SM, Elshemey WM. Quantitative structure-activity relationship and molecular docking revealed a potency of anti-hepatitis C virus drugs against human corona viruses. J Med Virol. 2017;89:1040-7.
Ahn DG, Choi JK, Taylor DR, Oh JW. Biochemical characterization of a recombinant SARS coronavirus nsp12 RNA-dependent RNA polymerase capable of copying viral RNA templates. Archives Virology. 2012;157(11):2095-104.
Elfiky AA. Anti-HCV, nucleotide inhibitors, repurposing against COVID-19. Life Sci. 2020:117477.
Elfiky AA, Ismail AM. Molecular docking revealed the binding of nucleotide/side inhibitors to Zika viral polymerase solved structures. SAR QSAR Environmental Res. 2018;29(5):409-18.
Kirchdoerfer RN, Ward AB. Structure of the SARS-CoVnsp12 polymerase bound to nsp7 and nsp8 co-factors. Nature Communications. 2019;10(1):1-9.
Subissi L, Posthuma CC, Collet A, Dobbe ZJC, Gorbalenya AE, Decroly E, et al. One severe acute respiratory syndrome coronavirus protein complex integrates processive RNA polymerase and exonuclease activities. Proceedings National Academy Sci. 2014;111(37):3900-9.
Tortorici MA, Veesler D. Structural insights into coronavirus entry. Advances Virus Res. 2019;105:93-116.
Walls AC, Park YJ, Tortorici MA, Wall A, McGuire AT, Veesler D. Structure, function, and antigenicity of the SARS-CoV-2 spike glycoprotein. Cell. 2020; 181(2):281-96.
Millet JK, Whittaker GR. Host cell proteases: Critical determinants of coronavirus tropism and pathogenesis. Virus Res. 2015;202:120-34.
Gordon CJ, Tchesnokov EP, Feng JY, Porter DP, Gotte M. The anti-viral compound remdesivir potently inhibits RNA-dependent RNA polymerase from Middle East respiratory syndrome coronavirus. J Biological Chemistry. 2020;295(15):4773-9.
Agostini ML, Andres EL, Sims AC, Graham RL, Sheahan TP, Lu X, et al. Coronavirus susceptibility to the antiviral remdesivir (GS-5734) is mediated by the viral polymerase and the proofreading exoribonuclease. M Bio. 2018;9(2):e00221-18.
World Health Organization. WHO R and D Blueprint Ad-hoc Expert Consultation on clinical trials for Ebola Therapeutics. Available at: https://www.who. int/ebola/drc-2018/summaries-of-evidence-experimental-therapeutics.pdf?ua=1. Accessed on 21 June 2020.
Woo PC, Lau SK, Huang Y, Yuen KY. Coronavirus diversity, phylogeny and interspecies jumping. Experimental Biology Med. 2009;234(10):1117-27.
Wang M, Cao R, Zhang L, Yang X, Liu J, Xu M, et al. Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro. Cell Res. 2020;30(3):269-71.
Choy KT, Wong AY, Kaewpreedee P, Sia SF, Chen D, Hui KP, et al. Remdesivir, lopinavir, emetine, and homoharringtonine inhibit SARS-CoV-2 replication in vitro. Antiviral Res. 2020:104786.
Grein J, Ohmagari N, Shin D, Diaz G, Asperges E, Castagna A, et al. Compassionate use of remdesivir for patients with severe Covid-19. New England J Med. 2020;382:2327-36.
U.S National Librabry of Medical Clinical Trials Registry. Trial of Treatments for COVID-19 in Hospitalized Adults (discovery). Available at: https://clinicaltrials.gov/ct2/show/NCT04315948?term=NCT04315948&draw=2&rank=1.
U.S National Library of Medical Clinical Trials Registry. Adaptive COVID-19 Treatment Trial (ACTT). Available at: https://clinicaltrials.gov/ct2/ show/NCT04280705?term=NCT04280705&draw=2&rank=1. Accessed on 21 June 2020.
National Institute of Allergy and Infectious Diseases. NIH Clinical Trial Shows Remdesivir Accelerates Recovery from Advanced COVID-19. Available at: https://www.niaid.nih.gov/news-events/nih-clinical-trial-shows-remdesivir-accelerates-recovery-advanced-covid-19. Accessed on 21 June 2020.
U.S National Librabry of Medical Clinical Trials Registry. Study to Evaluate the Safety and Antiviral Activity of Remdesivir (GS-5734™) in Participants with Severe Coronavirus Disease (COVID-19). Available at: https://clinicaltrials.gov/ct2/show/ NCT04292899?term=NCT04292899&draw=2&rank=1. Accessed on 21 June 2020.
U.S National Library of Medical Clinical Trials Registry. Study to evaluate the Safety and Antiviral Activity of Remdesivir (GS-5734) in Participants with Moderate Coronavirus Disease (COVID-190 Compared to Standard of Care Treatment. Available at: https://clinicaltrials.gov/ct2/show/NCT04292730 ?term=NCT04292730&draw=2&rank=1. Accessed on 21 June 2020.
U.S National Library of Medical Clinical Trials Registry. Study to Evaluate the Safety and Antiviral Activity of Remdesivir (GS-5734™) in Participants with Moderate Coronavirus Disease (COVID-19) Compared to Standard of Care Treatment. Available at: https://clinicaltrials.gov/ct2/show/NCT04321616 ?term=NCT04321616&draw=2&rank=1. Accessed on 21 June 2020.
U.S National Library of Medical Clinical Trials Registry. Multicenter, Retrospective Study of the Effects of Remdesivir in the Treatment of Severe Covid-19 Infections (REMDECO-19). Available at: https://clinicaltrials.gov/ct2/show/NCT04365725?term=remdesivir&draw=6&rank=3. Accessed on 21 June 2020.
U.S National Library of Medical Clinical Trials Registry. A Trial of Remdesivir in Adults with Mild and Moderate COVID-19. Available at: https://clinicaltrials.gov/ct2/show/NCT04252664?term=remdesivir&draw=2&rank=2. Accessed on 21 June 2020.
Wang Y, Zhang D, Du G, Du R, Zhao J, Jin Y, et al. Remdesivir in adults with severe COVID-19: a randomized, double-blind, placebo-controlled, multicentre trial. Lancet. 2020;395:1569-78.
U.S National Library of Medical Clinical trials Registry. Recruiting Studies | COVID-19 | Phase 3. Available at: https://clinicaltrials.gov/ct2/results? cond=COVID-19&Search=Apply&recrs=a&age_v= &gndr=&type=&rslt=&phase=2. Accessed on 21 June 2020.