Molnupiravir is the 5′-isobutyrate prodrug of the antiviral ribonucleoside analogue β-D-N4-hydroxycytidine (NHC) [1]. Molnupiravir rapidly appears in plasma and is converted to the triphosphate form in cells, which is incorporated into viral RNA in place of cytosine or uracil by RNA-dependent RNA polymerase (RdRp), causing a break of viral replication[2]. Molnupiravir has been used as an oral antiviral drug to inhibit various RNA virus infections in different cell models and animal models[3].
In vitro, Molnupiravir treatment for 48 hours significantly inhibited the replication of WT SARS-CoV-2 and Omicron SARS-CoV-2 in Calu-3 cells, with IC50 values of 1.965μM and 0.7556μM, respectively[4]. 62.5 μM of Molnupiravir treatment for 72 hours inhibited viral release and replication in fcwf-4 cells infected with Alphacoronavirus suis[5]. Treatment of Vero cells with 96μM of Molnupiravir for 1 hour significantly reduced the viral genome copy number and viral titer of porcine epidemic diarrhea virus, and maintained the normal morphology of the cells[6].
In vivo, Molnupiravir treatment via intragastrical administration (500mg/kg) once 2 hours before MERS-CoV infection, as well as at 12 hours, 24 hours, and 48 hours after infection, can improve lung function, reduce virus titer, and alleviate weight loss in hDPP4 288/330 gene-modified mice [7]. Oral administration of Molnupiravir (100mg/kg) twice daily to female ferrets within 3.5 days after infection with H1N1 influenza virus significantly reduced viral load, alleviated fever, airway epithelial tissue pathological changes, and inflammation[8].
References:
[1] Kumar D, Trivedi N. Disease-drug and drug-drug interaction in COVID-19: Risk and assessment[J]. Biomedicine & Pharmacotherapy, 2021, 139: 111642.
[2] Bekheit M S, Panda S S, Girgis A S. Potential RNA-dependent RNA polymerase (RdRp) inhibitors as prospective drug candidates for SARS-CoV-2[J]. European Journal of Medicinal Chemistry, 2023, 252: 115292.
[3] Malek R J, Bill C A, Vines C M. Clinical drug therapies and biologicals currently used or in clinical trial to treat COVID-19[J]. Biomedicine & Pharmacotherapy, 2021, 144: 112276.
[4] Li P, Wang Y, Lavrijsen M, et al. SARS-CoV-2 Omicron variant is highly sensitive to molnupiravir, nirmatrelvir, and the combination[J]. Cell research, 2022, 32(3): 322-324.
[5] Doki T, Shinohara K, To K, et al. Molnupiravir Inhibits Replication of Multiple Alphacoronavirus suis Strains in Feline Cells[J]. Pathogens, 2025, 14(8): 787.
[6] Huang Z X, Zhou S T, Yang Z B, et al. Molnupiravir inhibits porcine epidemic diarrhea virus infection in vitro[J]. Viruses, 2023, 15(6): 1317.
[7] Sheahan T P, Sims A C, Zhou S, et al. An orally bioavailable broad-spectrum antiviral inhibits SARS-CoV-2 in human airway epithelial cell cultures and multiple coronaviruses in mice[J]. Science translational medicine, 2020, 12(541): eabb5883.
[8] Toots M, Yoon J J, Cox R M, et al. Characterization of orally efficacious influenza drug with high resistance barrier in ferrets and human airway epithelia[J]. Science translational medicine, 2019, 11(515): eaax5866.