A COMPREHENSIVE REVIEW OF MOLNUPIRAVIR, NOVEL ANTIVIRAL DRUG FOR COVID-19
DOI:
https://doi.org/10.22159/ijcpr.2025v17i3.55037Keywords:
Molnupiravir, COVID-19, Evidences of efficacy and safetyAbstract
Effective oral antiviral drugs are still lacking despite improvements in COVID-19 management. Finding efficient and safe treatment against COVID-19 has become more important as a result of the discovery of novel SARS-CoV-2 mutations and the reporting of individuals with severe illness. A well-known viral RdRp inhibitor called molnupiravir has remarkably mutagenic effects on viral RNA. In the ongoing hunt for innovative antiviral drugs with acceptable efficacy and safety profiles against COVID-19, RdRp has been a priority target due to its significant role in the replication and transcription process of SARS-CoV-2 RNA. The possible evidences of efficacy and safety of molnupiravir in the treatment of COVID-19 are explored in the current review.
Downloads
References
Shukla AK, Misra S. An overview of post COVID sequelae. J Basic Clin Physiol Pharmacol. 2022 Apr 15;33(6):715-26. doi: 10.1515/jbcpp-2022-0057, PMID 35428040.
Singh AK, Singh A, Singh R, Misra A. Molnupiravir in COVID-19: a systematic review of literature. Diabetes Metab Syndr. 2021 Dec;15(6):102329. doi: 10.1016/j.dsx.2021.102329, PMID 34742052.
Jayk Bernal A, Gomes DA, Silva MM, Musungaie DB, Kovalchuk E, Gonzalez A, Delos Reyes V. Molnupiravir for oral treatment of COVID-19 in nonhospitalized patients. N Engl J Med. 2022 Feb 10;386(6):509-20. doi: 10.1056/NEJMoa2116044, PMID 34914868.
Tenforde MW, Kim SS, Lindsell CJ, Billig Rose E, Shapiro NI, Files DC. Symptom duration and risk factors for delayed return to usual health among outpatients with COVID-19 in a multistate health care systems network United States. MMWR Morb Mortal Wkly Rep. 2020;69(30):993-8. doi: 10.15585/mmwr.mm6930e1, PMID 32730238.
Rosenberg ES, Holtgrave DR, Dorabawila V, Conroy M, Greene D, Lutterloh E. New COVID-19 cases and hospitalizations among adults by vaccination status new York. MMWR Morb Mortal Wkly Rep. 2021 Aug 27;70(34):1150-5. doi: 10.15585/mmwr.mm7034e1, PMID 34437517.
Bajema KL, Dahl RM, Prill MM, Meites E, Rodriguez Barradas MC, Marconi VC. Effectiveness of COVID-19 mRNA vaccines against COVID-19-associated hospitalization five veterans affairs medical centers united states. MMWR Morb Mortal Wkly Rep. 2021;70(37):1294-9. doi: 10.15585/mmwr.mm7037e3, PMID 34529636.
Hurt AC, Wheatley AK. Neutralizing antibody therapeutics for COVID-19. Viruses. 2021;13(4):628. doi: 10.3390/v13040628, PMID 33916927.
Recovery Collaborative Group. Casirivimab and imdevimab in patients admitted to hospital with COVID-19 (Recovery): a randomised controlled open-label platform trial. Lancet. 2022 Feb 12;399(10325):665-76. doi: 10.1016/S0140-6736(22)00163-5, PMID 35151397.
Gottlieb RL, Nirula A, Chen P, Boscia J, Heller B, Morris J. Effect of bamlanivimab as monotherapy or in combination with etesevimab on viral load in patients with mild to moderate COVID-19: a randomized clinical trial. JAMA. 2021 Feb 16;325(7):632-44. doi: 10.1001/jama.2021.0202, PMID 33475701.
Gupta A, Gonzalez Rojas Y, Juarez E, Crespo Casal M, Moya J, Falci DR. Early treatment for COVID-19 with SARS-CoV-2 neutralizing antibody sotrovimab. N Engl J Med. 2021 Nov 18;385(21):1941-50. doi: 10.1056/NEJMoa2107934, PMID 34706189.
Planas D, Veyer D, Baidaliuk A, Staropoli I, Guivel Benhassine F, Rajah MM. Reduced sensitivity of SARS-CoV-2 variant delta to antibody neutralization. Nature. 2021 Aug 12;596(7871):276-80. doi: 10.1038/s41586-021-03777-9, PMID 34237773.
European Centre for Disease Prevention and Control European Centre for Disease Prevention and Control (ECDC). Stockholm (Sweden): Risk assessment: SARSCoV-2-increased circulation of variants of concern and vaccine roll out in the EU/EEA, 14th update; 2021 Feb 15.
US Food and Drug Administration. In: Fact sheet for health care providers emergency use authorization (EUA) of bamlanivimab and etesevimab. Available from: https://www.fda.gov/media/145802/download. [Last accessed on 27 Jul 2023].
US Food and Drug Administration. Fact sheet health care providers emerg use authorization (EUA) regen-cov (Casirivimab with imdevimab). Available from https://www.fda.gov/media/145611/download. [Last accessed on 27 Jul 2023].
Cao Y, Wang J, Jian F, Xiao T, Song W, Yisimayi A. Omicron escapes the majority of existing SARS-CoV-2 neutralizing antibodies. Nature. 2022 Feb;602(7898):657-63. doi: 10.1038/s41586-021-04385-3, PMID 35016194.
Singh AK, Singh A, Singh R, Misra A. Molnupiravir in COVID-19: a systematic review of literature. Diabetes Metab Syndr. 2021;6(6):102329. doi: 10.1016/j.dsx.2021.102329, PMID 34742052.
Singh AK, Singh A, Singh R, Misra A. An updated practical guideline on use of molnupiravir and comparison with agents having emergency use authorization for treatment of COVID-19. Diabetes & Metabolic Syndrome: Clinical Research & Reviews. 2022;16(2):102396. doi: 10.1016/j.dsx.2022.102396.
Sharma P, Behl T, Sharma N, Singh S, Grewal AS, Albarrati A. COVID-19 and diabetes: association intensify risk factors for morbidity and mortality. Biomed Pharmacother. 2022 Jul;151:113089. doi: 10.1016/j.biopha.2022.113089, PMID 35569351.
Sheahan TP, Sims AC, Zhou S, Graham RL, Pruijssers AJ, Agostini ML. An orally bioavailable broad spectrum antiviral inhibits SARS-CoV-2 in human airway epithelial cell cultures and multiple coronaviruses in mice. Sci Transl Med. 2020 Apr 29;12(541):eabb5883. doi: 10.1126/scitranslmed.abb5883, PMID 32253226.
Painter GR, Natchus MG, Cohen O, Holman W, Painter WP. Developing a direct acting orally available antiviral agent in a pandemic: the evolution of molnupiravir as a potential treatment for COVID-19. Curr Opin Virol. 2021;50:17-22. doi: 10.1016/j.coviro.2021.06.003, PMID 34271264.
Tian L, Pang Z, LI M, Lou F, An X, Zhu S. Molnupiravir and its antiviral activity against COVID-19. Front Immunol. 2022;13:855496. doi: 10.3389/fimmu.2022.855496, PMID 35444647.
GOV UK. First oral antiviral for COVID-19 lagevrio (molnupiravir) approved by mhra. Available from: https://www.gov.uk/government/news/first-oral-antiviral-for-covid-19lagevrio-molnupiravir-approved-by-mhra#:~:text=The%20antiviral%20Lagevrio%20(molnupiravir)%20is,Agency%20(MHRA)%20announced%20today. [Last accessed on 26 Jul 2023].
Merck news release. Merck and ridgebacks molnupiravir receives U. S. FDA emergency use authorization for the treatment of high risk adults with mild to moderate COVID-19. Available from: https://www.merck.com/news/merck-and-ridgebacks-molnupiravir-receives-u-s-fda-emergency-use-authorization-for-the-treatment-of-high-risk-adults-with-mild-to-moderate-covid-19. [Last accessed on 03 Mar 2023].
Antiviral Therapy. COVID-19 treatment guidelines. Available from: https://www.covid19treatmentguidelines.nih.gov/therapies/antiviral-therapy. [Last accessed on 03 Mar 2023].
Wahl A, Gralinski LE, Johnson CE, Yao W, Kovarova M, Dinnon KH. SARS-CoV-2 infection is effectively treated and prevented by EIDD-2801. Nature. 2021;591(7850):451-7. doi: 10.1038/s41586-021-03312-w, PMID 33561864.
Merck. Fact sheet for healthcare providers: emergency use authorization for molnupiravir]. Available from: https://www.com.merck/eua/molnupiravir-hcp-fact-sheet.pdf. [Last accessed on 03 Mar 2023]
Smith EC, Blanc H, Surdel MC, Vignuzzi M, Denison MR. Coronaviruses lacking exoribonuclease activity are susceptible to lethal mutagenesis: evidence for proofreading and potential therapeutics. Plos Pathog. 2013 Aug;9(8):e1003565. doi: 10.1371/journal.ppat.1003565, PMID 23966862.
Agostini ML, Pruijssers AJ, Chappell JD, Gribble J, LU X, Andres EL. Small-molecule antiviral β-d-n4-hydroxycytidine inhibits a proofreading-intact coronavirus with a high genetic barrier to resistance. J Virol. 2019;93(24):e01348-19. doi: 10.1128/JVI.01348-19, PMID 31578288.
Sledziewska Gojska E, Janion C. Effect of proofreading and dam instructed mismatch repair systems on N4-hydroxycytidine induced mutagenesis. Mol Gen Genet. 1982;186(3):411-8. doi: 10.1007/BF00729462, PMID 6750321.
Tejero H, Montero F, Nuno JC. Theories of lethal mutagenesis: from error catastrophe to lethal defection. Curr Top Microbiol Immunol. 2016;392:161-79. doi: 10.1007/82_2015_463, PMID 26210988.
Hashemian SM, Pourhanifeh MH, Hamblin MR, Shahrzad MK, Mirzaei H. RdRp inhibitors and COVID-19: is molnupiravir a good option? Biomed Pharmacother. 2022 Feb;146:112517. doi: 10.1016/j.biopha.2021.112517, PMID 34902743.
Sheahan TP, Sims AC, Zhou S, Graham RL, Pruijssers AJ, Agostini ML. An orally bioavailable broad spectrum antiviral inhibits SARS-CoV-2 in human airway epithelial cell cultures and multiple coronaviruses in mice. Sci Transl Med. 2020;12(541):eabb5883. doi: 10.1126/scitranslmed.abb5883, PMID 32253226.
Urakova N, Kuznetsova V, Crossman DK, Sokratian A, Guthrie DB, Kolykhalov AA. β-d-N4-Hydroxycytidine is a potent anti-alphavirus compound that induces a high level of mutations in the viral genome. J Virol. 2018;92(3):e01965-17. doi: 10.1128/JVI.01965-17, PMID 29167335.
Rosenke K, Hansen F, Schwarz B, Feldmann F, Haddock E, Rosenke R. Orally delivered MK-4482 inhibits SARS-CoV-2 replication in the syrian hamster model. Nat Commun. 2021;12(1):2295. doi: 10.1038/s41467-021-22580-8, PMID 33863887.
Gordon CJ, Tchesnokov EP, Schinazi RF, Gotte M. Molnupiravir promotes SARS-CoV-2 mutagenesis via the RNA template. J Biol Chem. 2021;297(1):100770. doi: 10.1016/j.jbc.2021.100770, PMID 33989635.
Kabinger F, Stiller C, Schmitzova J, Dienemann C, Kokic G, Hillen HS. Mechanism of molnupiravir induced SARS-CoV-2 mutagenesis. Nat Struct Mol Biol. 2021;28(9):740-6. doi: 10.1038/s41594-021-00651-0, PMID 34381216.
Atmar RL, Finch N. New perspectives on antimicrobial agents: molnupiravir and nirmatrelvir/ritonavir for treatment of COVID-19. Antimicrob Agents Chemother. 2022;66(8):e0240421. doi: 10.1128/aac.02404-21, PMID 35862759.
Sheahan TP, Sims AC, Zhou S, Graham RL, Pruijssers AJ, Agostini ML. An orally bioavailable broad spectrum antiviral inhibits SARS-CoV-2 in human airway epithelial cell cultures and multiple coronaviruses in mice. Sci Transl Med. 2020;12(541):eabb5883. doi: 10.1126/scitranslmed.abb5883, PMID 32253226.
Abdelnabi R, Foo CS, Kaptein SJ, Zhang X, DO TN, Langendries L. The combined treatment of molnupiravir and favipiravir results in a potentiation of antiviral efficacy in a SARS-CoV-2 hamster infection model. E Biomedicine. 2021;72:103595. doi: 10.1016/j.ebiom.2021.103595, PMID 34571361.
DO TN, Donckers K, Vangeel L, Chatterjee AK, Gallay PA, Bobardt MD. A robust SARS-CoV-2 replication model in primary human epithelial cells at the air liquid interface to assess antiviral agents. Antiviral Res. 2021 Aug;192:105122. doi: 10.1016/j.antiviral.2021.105122, PMID 34186107.
Zhao J, Guo S, YI D, LI Q, MA L, Zhang Y. A cell based assay to discover inhibitors of SARS-CoV-2 RNA dependent RNA polymerase. Antiviral Res. 2021;190:105078. doi: 10.1016/j.antiviral.2021.105078, PMID 33894278.
Cox RM, Wolf JD, Plemper RK. Therapeutically administered ribonucleoside analogue MK-4482/EIDD-2801 blocks SARS-CoV-2 transmission in ferrets. Nat Microbiol. 2021;6(1):11-8. doi: 10.1038/s41564-020-00835-2, PMID 33273742.
Toots M, Yoon JJ, Cox RM, Hart M, Sticher ZM, Makhsous N. Characterization of orally efficacious influenza drug with high resistance barrier in ferrets and human airway epithelia. Sci Transl Med. 2019;11(515):eaax5866. doi: 10.1126/scitranslmed.aax5866, PMID 31645453.
Rosenke K, Hansen F, Schwarz B, Feldmann F, Haddock E, Rosenke R. Orally delivered MK-4482 inhibits SARS-CoV-2 replication in the syrian hamster model. Res Sq. 2020 Oct 8. doi: 10.21203/rs.3.rs-86289/v1, PMID 33052329.
Wahl A, Gralinski LE, Johnson CE, Yao W, Kovarova M, Dinnon KH 3rd. SARS-CoV-2 infection is effectively treated and prevented by EIDD-2801. Nature. 2021;591(7850):451-7. doi: 10.1038/s41586-021-03312-w, PMID 33561864.
Sheahan TP, Sims AC, Zhou S, Graham RL, Pruijssers AJ, Agostini ML. An orally bioavailable broad spectrum antiviral inhibits SARS-CoV-2 in human airway epithelial cell cultures and multiple coronaviruses in mice. Sci Transl Med. 2020;12(541):eabb5883. doi: 10.1126/scitranslmed.abb5883, PMID 32253226.
Kumar D, Trivedi N. Disease drug and drug-drug interaction in COVID-19: risk and assessment. Biomed Pharmacother. 2021 Jul;139:111642. doi: 10.1016/j.biopha.2021.111642, PMID 33940506.
Ribeiro IG, Coelho Dos Reis JG, Fradico JR, Costa Rocha IA, Silva LD, Fonseca LA. Remodeling of immunological biomarkers in patients with chronic hepatitis C treated with direct acting antiviral therapy. Antiviral Res. 2021;190:105073. doi: 10.1016/j.antiviral.2021.105073, PMID 33887350.
Parsons TL, Kryszak LA, Marzinke MA. Development and validation of assays for the quantification of β-D-N4-hydroxycytidine in human plasma and β-D-N4-hydroxycytidine triphosphate in peripheral blood mononuclear cell lysates. J Chromatogr B Analyt Technol Biomed Life Sci. 2021;1182:122921. doi: 10.1016/j.jchromb.2021.122921, PMID 34555541.
Schaller MA, Sharma Y, Dupee Z, Nguyen D, Uruena J, Smolchek R. Ex vivo SARS-CoV-2 infection of human lung reveals heterogeneous host defense and therapeutic responses. JCI Insight. 2021;6(18):e148003. doi: 10.1172/jci.insight.148003, PMID 34357881.
Cox RM, Wolf JD, Plemper RK. Therapeutically administered ribonucleoside analogue MK‐4482/EIDD‐2801 blocks SARS‐CoV‐2 transmission in ferrets. Nat Microbiol. 2021;6(1):11-8. doi: 10.1038/s41564-020-00835-2, PMID 33273742.
Ebenezer O, Jordaan MA, Ogunsakin RE, Shapi M. Potential SARS‐COV preclinical (in vivo) compounds targeting COVID‐19 main protease: a meta‐analysis and molecular docking studies. Hippokratia. 2020;24(3):99-106. PMID 34239286.
Han B, Song Y, LI C, Yang W, MA Q, Jiang Z. Safety tolerability and immunogenicity of an inactivated SARS-CoV-2 vaccine (CoronaVac) in healthy children and adolescents: a double blind randomised controlled phase 1/2 clinical trial. Lancet Infect Dis. 2021 Dec;21(12):1645-53. doi: 10.1016/S1473-3099(21)00319-4, PMID 34197764.
Painter WP, Holman W, Bush JA, Almazedi F, Malik H, Eraut NC. Human safety tolerability and pharmacokinetics of molnupiravir a novel broad spectrum oral antiviral agent with activity against SARS-CoV-2. Antimicrob Agents Chemother. 2021 May 1;65(5):e02428-20. doi: 10.1128/AAC.02428-20, PMID 33649113.
Khoo SH, Fitzgerald R, Fletcher T, Ewings S, Jaki T, Lyon R. Optimal dose and safety of molnupiravir in patients with early SARS-CoV-2: a Phase I, open-label, dose escalating randomized controlled study. J Antimicrob Chemother. 2021 Nov 12;76(12):3286-95. doi: 10.1093/jac/dkab318, PMID 34450619.
Fischer W, Eron JJ, Holman W, Cohen MS, Fang L, Szewczyk LJ. Molnupiravir an oral antiviral treatment for COVID-19. medRxiv; 2021 Jun 17;2021:21258639. doi: 10.1101/2021.06.17.21258639.
Clinical trials. The safety of molnupiravir (EIDD-2801) and its effect on viral shedding of SARS-CoV-2. Available from: https://clinicaltrials.gov/ct2/show/NCT04405739. [Last accessed on 3 Mar 2023].
Merck. Com Merck and ridgeback's investigational oral antiviral molnupiravir reduced the risk of hospitalization or death by approximately 50 percent compared to placebo for patients with mild or moderate COVID-19 in positive interim analysis of phase 3 study. Available from: https://www.merck.com/news/merckand-ridgebacks-investigational-oral-antiviral-molnupiravir-reduced-the-riskof-hospitalization-or-death-by-approximately-50-percent-compared-toplacebo-for-patients-with-mild-or-moderat. [Last accessed on 3 Mar 2023].
Merck. Merck and ridgeback biotherapeutics provide update on progress of clinical development program for molnupiravir an investigational oral therapeutic for the treatment of mild to moderate COVID-19. Available from: https://www.merck.com/news/merck-and-ridgeback-biotherapeutics-provide-update-on-progress-of-clinical-development-program-for-molnupiravir-aninvestigational-oral-therapeutic-for-the-treatment-of-mild-to-moderate-covid-19/#:~:text=Merck%20and%20Ridgeback%20Biotherapeutics%20plan.
Clinical Trail. A phase III, randomized multi-centre double blind placebo controlled study to evaluate efficacy safety and immunogenicity of novel corona virus-2019-nCov vaccine candidate of M/s cadila healthcare limited. Available from: https://ctri.nic.in/clinicaltrials/showallp.php?mid1=51254andEncHid=anduserName=ZyCoV-D. [Last accessed on 26 Jul 2023].
The Print. Optimus announces interim clinical results from phase III clinical trials of molnupiravir conducted in India. Available from: www.//https.print.in/ani-press-releases/optimus-announces-interim-clinical-results-from-phase-iii-clinical-trials-of-molnupiravir-conducted-in-india/699993. [Last accessed on 3 Mar 2023].
Jayk Bernal A, Gomes DA Silva MM, Musungaie DB, Kovalchuk E, Gonzalez A, Delos Reyes V. Molnupiravir for oral treatment of Covid-19 in nonhospitalized patients. N Engl J Med. 2022 Feb 10;386(6):509-20. doi: 10.1056/NEJMoa2116044, PMID 34914868.
DE Vito A, Colpani A, Bitti A, Zauli B, Meloni MC, Fois M. Safety and efficacy of molnupiravir in SARS-CoV-2-infected patients: a real life experience. J Med Virol. 2022 Nov;94(11):5582-8. doi: 10.1002/jmv.28011, PMID 35855627.
Zou R, Peng L, Shu D, Zhao L, Lan J, Tan G. Antiviral efficacy and safety of molnupiravir against omicron variant infection: a randomized controlled clinical trial. Front Pharmacol. 2022 Jun 15;13:939573. doi: 10.3389/fphar.2022.939573, PMID 35784723.
Merck. Fact sheet for healthcare providers: emergency use authorization for molnupiravir. Com. Available from: https://www.merck/eua/molnupiravir-hcp-fact-sheet.pdf. [Last accessed on 03 Mar 2023].
Merck. Merck briefing information for the Nov 30 2021 meeting of the antimicrobial drugs advisory committee. Available https://www.fda.gov/media/154421/download. [Last accessed on 03 Mar 2023].
Arribas JR, Bhagani S, Lobo SM, Khaertynova I, Mateu L, Fishchuk R. Randomized trial of molnupiravir or placebo in patients hospitalized with covid-19. NEJM Evid. 2022;1(2):EVIDoa2100044. doi: 10.1056/EVIDoa2100044, PMID 38319178.
Published
How to Cite
Issue
Section
Copyright (c) 2025 AJAY KUMAR SHUKLA, SAURAV MISRA

This work is licensed under a Creative Commons Attribution 4.0 International License.