The Triple Combination of Remdesivir (GS-441524), Molnupiravir and Ribavirin is Highly Efficient in Inhibiting Coronavirus Replication in Human Nasal Airway Epithelial Cell Cultures and in a Hamster Infection Model

Overview

Journal Antiviral Res

Publisher Elsevier

Date 2024 Sep 5

PMID 39237005

Authors

Thuc Nguyen Dan Do

Rana Abdelnabi

Bernadett Boda

Samuel Constant

Johan Neyts

Dirk Jochmans

Affiliations

Soon will be listed here.

Abstract

The use of fixed dose-combinations of antivirals with different mechanisms of action has proven key in the successful treatment of infections with HIV and HCV. For the treatment of infections with SARS-CoV-2 and possible future epi-/pandemic coronaviruses, it will be important to explore the efficacy of combinations of different drugs, in particular to avoid resistance development, such as in patients with immunodeficiencies. This work explores the effect of a combination of 3 broad-spectrum antiviral nucleosides on the replication of coronaviruses. To that end, we made use of primary human airway epithelial cell (HAEC) cultures grown at the air-liquid interface that were infected with the beta coronavirus OC43. We found that the triple combination of GS-441524 (the parent nucleoside of remdesivir), molnupiravir and ribavirin resulted in a more pronounced antiviral efficacy than what could be expected from a purely additive antiviral effect. The potency of this triple combination was next tested in SARS-CoV-2 infected hamsters in a prophylactic setup. To that end, for each of the drugs, intentionally suboptimal or even ineffective doses were selected. Yet, in the lungs of all hamsters that received triple prophylactic therapy (but not in those that received the respective double combinations) no infectious virus was detectable. Our findings indicate that co-administration of approved drugs for the treatment of coronavirus infections should be further explored but also against other families of viruses with epidemic and pandemic potential for which no effective antiviral treatment is available.

Citing Articles

Combinations of approved oral nucleoside analogues confer potent suppression of alphaviruses and .

Verwimp S, Wagoner J, Arenas E, De Coninck L, Abdelnabi R, Hyde J bioRxiv. 2025; .

PMID: 39896535 PMC: 11785157. DOI: 10.1101/2025.01.24.633564.

References

Tapparel C, Sobo K, Constant S, Huang S, van Belle S, Kaiser L . Growth and characterization of different human rhinovirus C types in three-dimensional human airway epithelia reconstituted in vitro. Virology. 2013; 446(1-2):1-8. DOI: 10.1016/j.virol.2013.06.031. View

Hung I, Lung K, Tso E, Liu R, Chung T, Chu M . Triple combination of interferon beta-1b, lopinavir-ritonavir, and ribavirin in the treatment of patients admitted to hospital with COVID-19: an open-label, randomised, phase 2 trial. Lancet. 2020; 395(10238):1695-1704. PMC: 7211500. DOI: 10.1016/S0140-6736(20)31042-4. View

Shyr Z, Cheng Y, Lo D, Zheng W . Drug combination therapy for emerging viral diseases. Drug Discov Today. 2021; 26(10):2367-2376. PMC: 8139175. DOI: 10.1016/j.drudis.2021.05.008. View

Ferron F, Subissi L, Silveira De Morais A, Le N, Sevajol M, Gluais L . Structural and molecular basis of mismatch correction and ribavirin excision from coronavirus RNA. Proc Natl Acad Sci U S A. 2017; 115(2):E162-E171. PMC: 5777078. DOI: 10.1073/pnas.1718806115. View

Jayk Bernal A, Gomes da Silva M, Musungaie D, Kovalchuk E, Gonzalez A, Delos Reyes V . Molnupiravir for Oral Treatment of Covid-19 in Nonhospitalized Patients. N Engl J Med. 2021; 386(6):509-520. PMC: 8693688. DOI: 10.1056/NEJMoa2116044. View

Abdelnabi R, Foo C, Kaptein S, Zhang X, Do T, Langendries L . The combined treatment of Molnupiravir and Favipiravir results in a potentiation of antiviral efficacy in a SARS-CoV-2 hamster infection model. EBioMedicine. 2021; 72:103595. PMC: 8461366. DOI: 10.1016/j.ebiom.2021.103595. View

Toussi S, Hammond J, Gerstenberger B, Anderson A . Therapeutics for COVID-19. Nat Microbiol. 2023; 8(5):771-786. DOI: 10.1038/s41564-023-01356-4. View

Eslami G, Mousaviasl S, Radmanesh E, Jelvay S, Bitaraf S, Simmons B . The impact of sofosbuvir/daclatasvir or ribavirin in patients with severe COVID-19. J Antimicrob Chemother. 2020; 75(11):3366-3372. PMC: 7529105. DOI: 10.1093/jac/dkaa331. View

Hartman N, AHLUWALIA G, Cooney D, Mitsuya H, Kageyama S, Fridland A . Inhibitors of IMP dehydrogenase stimulate the phosphorylation of the anti-human immunodeficiency virus nucleosides 2',3'-dideoxyadenosine and 2',3'-dideoxyinosine. Mol Pharmacol. 1991; 40(1):118-24. View

10.

Focosi D, Maggi F, DAbramo A, Nicastri E, Sullivan D . Antiviral combination therapies for persistent COVID-19 in immunocompromised patients. Int J Infect Dis. 2023; 137:55-59. DOI: 10.1016/j.ijid.2023.09.021. View

11.

Nystrom K, Wanrooij P, Waldenstrom J, Adamek L, Brunet S, Said J . Inosine Triphosphate Pyrophosphatase Dephosphorylates Ribavirin Triphosphate and Reduced Enzymatic Activity Potentiates Mutagenesis in Hepatitis C Virus. J Virol. 2018; 92(19). PMC: 6146798. DOI: 10.1128/JVI.01087-18. View

12.

Chen F, Chan K, Jiang Y, Kao R, Lu H, Fan K . In vitro susceptibility of 10 clinical isolates of SARS coronavirus to selected antiviral compounds. J Clin Virol. 2004; 31(1):69-75. PMC: 7128415. DOI: 10.1016/j.jcv.2004.03.003. View

13.

Paeshuyse J, Dallmeier K, Neyts J . Ribavirin for the treatment of chronic hepatitis C virus infection: a review of the proposed mechanisms of action. Curr Opin Virol. 2012; 1(6):590-8. DOI: 10.1016/j.coviro.2011.10.030. View

14.

Dixit N, Layden-Almer J, Layden T, Perelson A . Modelling how ribavirin improves interferon response rates in hepatitis C virus infection. Nature. 2004; 432(7019):922-4. DOI: 10.1038/nature03153. View

15.

Abdelnabi R, Foo C, Jochmans D, Vangeel L, De Jonghe S, Augustijns P . The oral protease inhibitor (PF-07321332) protects Syrian hamsters against infection with SARS-CoV-2 variants of concern. Nat Commun. 2022; 13(1):719. PMC: 8847371. DOI: 10.1038/s41467-022-28354-0. View

16.

Abdelnabi R, Maes P, De Jonghe S, Weynand B, Neyts J . Combination of the parent analogue of remdesivir (GS-441524) and molnupiravir results in a markedly potent antiviral effect in SARS-CoV-2 infected Syrian hamsters. Front Pharmacol. 2023; 13:1072202. PMC: 9807602. DOI: 10.3389/fphar.2022.1072202. View

17.

Painter G, Natchus M, Cohen O, Holman W, Painter W . 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. PMC: 8277160. DOI: 10.1016/j.coviro.2021.06.003. View

18.

Jonsdottir H, Siegrist D, Julien T, Padey B, Bouveret M, Terrier O . Molnupiravir combined with different repurposed drugs further inhibits SARS-CoV-2 infection in human nasal epithelium in vitro. Biomed Pharmacother. 2022; 150:113058. PMC: 9057985. DOI: 10.1016/j.biopha.2022.113058. View

19.

Kabinger F, Stiller C, Schmitzova J, Dienemann C, Kokic G, Hillen H . Mechanism of molnupiravir-induced SARS-CoV-2 mutagenesis. Nat Struct Mol Biol. 2021; 28(9):740-746. PMC: 8437801. DOI: 10.1038/s41594-021-00651-0. View

20.

Li G, Hilgenfeld R, Whitley R, De Clercq E . Therapeutic strategies for COVID-19: progress and lessons learned. Nat Rev Drug Discov. 2023; 22(6):449-475. PMC: 10113999. DOI: 10.1038/s41573-023-00672-y. View