Published November 14, 2025 | Version v1
Journal article Open

Pan-viral efficacy profile of ribavirin: quantitative potency and safety landscape across virus families

Authors/Creators

  • 1. Industrial Technology Development Institute, Department of Science and Technology, Taguig, Philippines|University of the Philippines Los Baños, Laguna, Philippines

Description

This study quantifies ribavirin's pan-viral efficacy across seven virus families, compares it with favipiravir and remdesivir, and evaluates viral trait predictors alongside clinical concordance. In vitro analyses showed the highest potency against Flaviviridae and Paramyxoviridae, whereas Coronaviridae and Astroviridae were less susceptible, consistent with proofreading polymerases. Compared with its peers, remdesivir was most potent in coronavirus and filovirus models, while favipiravir exhibited the widest therapeutic window in orthomyxovirus assays. Family-wise means and bootstrap trait modeling identified the presence of a proofreading polymerase as the strongest positive predictor of log EC50, with negative-sense genomes also associated with reduced susceptibility. Clinical evidence aligned with laboratory findings, demonstrating robust benefits in hepatitis C and Lassa fever, with mixed effects in respiratory infections. Overall, the results provide an actionable benchmark for broad-spectrum drug selection and prioritization in preparedness and outbreak response.

Files

PHAR_article_159854.pdf

Files (1.3 MB)

Name Size Download all
md5:de20133878b2f9a51400b9e1099ee601
1.2 MB Preview Download
md5:26c2ba14fbbbefc917ee8a6cd10176e4
124.4 kB Preview Download

Additional details

Cites
Publication: 10.1128/mBio.00221-18 (DOI)
Publication: 10.1086/657315 (DOI)
Publication: 10.1073/pnas.1201130109 (DOI)
Publication: 10.1073/pnas.111085598 (DOI)
Publication: 10.1053/he.2000.5789 (DOI)
Publication: 10.1073/pnas.1718806115 (DOI)
Publication: 10.1016/j.antiviral.2013.09.015 (DOI)
Publication: 10.1002/rmv.483 (DOI)
Publication: 10.1016/j.virol.2015.02.039 (DOI)
Publication: 10.1056/NEJMoa1214853 (DOI)
Publication: 10.1128/JVI.79.3.1943-1947.2005 (DOI)
Publication: 10.4254/wjh.v8.i2.123 (DOI)
Publication: 10.1056/NEJM198601023140104 (DOI)
Publication: 10.1073/pnas.0508200103 (DOI)
Publication: 10.1038/s41598-023-29517-9 (DOI)
Publication: 10.1097/00006454-198702000-00004 (DOI)
Publication: 10.1126/scitranslmed.aal3653 (DOI)
Publication: 10.1371/journal.ppat.1003565 (DOI)
Publication: 10.1128/mr.58.3.491-562.1994 (DOI)
Publication: 10.1177/095632020101200501 (DOI)
Publication: 10.3851/IMP2125 (DOI)
Publication: 10.1016/j.ijantimicag.2020.106114 (DOI)
Publication: 10.1007/s00018-014-1695-z (DOI)
Publication: 10.1038/nature17180 (DOI)
Publication: 10.1128/AAC.02237-20 (DOI)
Publication: 10.1056/NEJMoa1316145 (DOI)
Has part
Figure: 10.3897/pharmacia.72.e159854.figure4 (DOI)
Figure: 10.3897/pharmacia.72.e159854.figure5 (DOI)
Figure: 10.3897/pharmacia.72.e159854.figure3 (DOI)
Figure: 10.3897/pharmacia.72.e159854.figure2 (DOI)
Figure: 10.3897/pharmacia.72.e159854.figure6 (DOI)
Figure: 10.3897/pharmacia.72.e159854.figure1 (DOI)
Other: 10.3897/pharmacia.72.e159854.suppl2 (DOI)
Other: 10.3897/pharmacia.72.e159854.suppl3 (DOI)
Other: 10.3897/pharmacia.72.e159854.suppl1 (DOI)

References

  • Agostini ML, Andres EL, Sims AC, Graham RL, Sheahan TP, Lu X, Smith EC, Case JB, Feng JY, Jordan R, Ray AS, Cihlar T, Siegel D, Mackman RL, Clarke MO, Baric RS, Denison MR (2018) Coronavirus Susceptibility to the Antiviral Remdesivir (GS-5734) is mediated by the viral polymerase and the proofreading exoribonuclease. mBio 9: e00221-18. https://doi.org/10.1128/mBio.00221-18
  • Bausch DG, Hadi CM, Khan SH, Lertora JJL (2010) Review of the literature and proposed guidelines for the use of oral ribavirin as postexposure prophylaxis for Lassa fever. Clinical Infectious Diseases: An Official Publication of the Infectious Diseases Society of America 51: 1435–1441. https://doi.org/10.1086/657315
  • Bouvet M, Imbert I, Subissi L, Gluais L, Canard B, Decroly E (2012) RNA 3'-end mismatch excision by the severe acute respiratory syndrome coronavirus nonstructural protein nsp10/nsp14 exoribonuclease complex. Proceedings of the National Academy of Sciences 109: 9372–9377. https://doi.org/10.1073/pnas.1201130109
  • Crotty S, Cameron CE, Andino R (2001) RNA virus error catastrophe: direct molecular test by using ribavirin. Proceedings of the National Academy of Sciences of the United States of America 98: 6895–6900. https://doi.org/10.1073/pnas.111085598
  • De Franceschi L, Fattovich G, Turrini F, Ayi K, Brugnara C, Manzato F, Noventa F, Stanzial AM, Solero P, Corrocher R (2000) Hemolytic anemia induced by ribavirin therapy in patients with chronic hepatitis C virus infection: role of membrane oxidative damage. Hepatology (Baltimore, Md. ) 31: 997–1004. https://doi.org/10.1053/he.2000.5789
  • Ferron F, Subissi L, Silveira De Morais AT, Le NTT, Sevajol M, Gluais L, Decroly E, Vonrhein C, Bricogne G, Canard B, Imbert I (2018) Structural and molecular basis of mismatch correction and ribavirin excision from coronavirus RNA. Proceedings of the National Academy of Sciences of the United States of America 115: E162–E171. https://doi.org/10.1073/pnas.1718806115
  • Furuta Y, Gowen BB, Takahashi K, Shiraki K, Smee DF, Barnard DL (2013) Favipiravir (T-705), a novel viral RNA polymerase inhibitor. Antiviral Research 100: 446–454. https://doi.org/10.1016/j.antiviral.2013.09.015
  • Graci JD, Cameron CE (2006) Mechanisms of action of ribavirin against distinct viruses. Reviews in Medical Virology 16: 37–48. https://doi.org/10.1002/rmv.483
  • Koonin EV, Dolja VV, Krupovic M (2015) Origins and evolution of viruses of eukaryotes: The ultimate modularity. Virology 479–480: 2–25. https://doi.org/10.1016/j.virol.2015.02.039
  • Koren G, King S, Knowles S, Phillips E (2003) Ribavirin in the treatment of SARS: A new trick for an old drug? CMAJ: Canadian Medical Association journal = journal de l'Association medicale canadienne 168: 1289–1292.
  • Lawitz E, Mangia A, Wyles D, Rodriguez-Torres M, Hassanein T, Gordon SC, Schultz M, Davis MN, Kayali Z, Reddy KR, Jacobson IM, Kowdley KV, Nyberg L, Subramanian GM, Hyland RH, Arterburn S, Jiang D, McNally J, Brainard D, Symonds WT, McHutchison JG, Sheikh AM, Younossi Z, Gane EJ (2013) Sofosbuvir for previously untreated chronic hepatitis C infection. The New England Journal of Medicine 368: 1878–1887. https://doi.org/10.1056/NEJMoa1214853
  • Leyssen P, Balzarini J, De Clercq E, Neyts J (2005) The predominant mechanism by which ribavirin exerts its antiviral activity in vitro against flaviviruses and paramyxoviruses is mediated by inhibition of IMP dehydrogenase. Journal of Virology 79: 1943–1947. https://doi.org/10.1128/JVI.79.3.1943-1947.2005
  • Loustaud-Ratti V, Debette-Gratien M, Jacques J, Alain S, Marquet P, Sautereau D, Rousseau A, Carrier P (2016) Ribavirin: Past, present and future. World Journal of Hepatology 8: 123–130. https://doi.org/10.4254/wjh.v8.i2.123
  • McCormick JB, King IJ, Webb PA, Scribner CL, Craven RB, Johnson KM, Elliott LH, Belmont-Williams R (1986) Lassa fever. Effective therapy with ribavirin. The New England Journal of Medicine 314: 20–26. https://doi.org/10.1056/NEJM198601023140104
  • Minskaia E, Hertzig T, Gorbalenya AE, Campanacci V, Cambillau C, Canard B, Ziebuhr J (2006) Discovery of an RNA virus 3'->5' exoribonuclease that is critically involved in coronavirus RNA synthesis. Proceedings of the National Academy of Sciences of the United States of America 103: 5108–5113. https://doi.org/10.1073/pnas.0508200103
  • Radoshitzky SR, Iversen P, Lu X, Zou J, Kaptein SJF, Stuthman KS, Van Tongeren SA, Steffens J, Gong R, Truong H, Sapre AA, Yang H, Xie X, Chia JJ, Song ZJ, Leventhal SM, Chan J, Shornikov A, Zhang X, Cowfer D, Yu H, Warren T, Cihlar T, Porter DP, Neyts J, Shi P-Y, Wells J, Bilello JP, Feng JY (2023) Expanded profiling of Remdesivir as a broad-spectrum antiviral and low potential for interaction with other medications in vitro. Scientific Reports 13: 3131. https://doi.org/10.1038/s41598-023-29517-9
  • Rodriguez WJ, Kim HW, Brandt CD, Fink RJ, Getson PR, Arrobio J, Murphy TM, McCarthy V, Parrott RH (1987) Aerosolized ribavirin in the treatment of patients with respiratory syncytial virus disease. The Pediatric Infectious Disease Journal 6: 159–163. https://doi.org/10.1097/00006454-198702000-00004
  • Sheahan TP, Sims AC, Graham RL, Menachery VD, Gralinski LE, Case JB, Leist SR, Pyrc K, Feng JY, Trantcheva I, Bannister R, Park Y, Babusis D, Clarke MO, Mackman RL, Spahn JE, Palmiotti CA, Siegel D, Ray AS, Cihlar T, Jordan R, Denison MR, Baric RS (2017) Broad-spectrum antiviral GS-5734 inhibits both epidemic and zoonotic coronaviruses. Science Translational Medicine 9: eaal3653. https://doi.org/10.1126/scitranslmed.aal3653
  • Smith EC, Blanc H, Surdel MC, Vignuzzi M, Denison MR (2013) Coronaviruses lacking exoribonuclease activity are susceptible to lethal mutagenesis: evidence for proofreading and potential therapeutics. PLoS pathogens 9: e1003565. https://doi.org/10.1371/journal.ppat.1003565
  • Strauss JH, Strauss EG (1994) The alphaviruses: gene expression, replication, and evolution. Microbiological Reviews 58: 491–562. https://doi.org/10.1128/mr.58.3.491-562.1994
  • Tam RC, Lau JY, Hong Z (2001) Mechanisms of action of ribavirin in antiviral therapies. Antiviral Chemistry & Chemotherapy 12: 261–272. https://doi.org/10.1177/095632020101200501
  • Thomas E, Ghany MG, Liang TJ (2012) The application and mechanism of action of ribavirin in therapy of hepatitis C. Antiviral Chemistry & Chemotherapy 23: 1–12. https://doi.org/10.3851/IMP2125
  • Tong S, Su Y, Yu Y, Wu C, Chen J, Wang S, Jiang J (2020) Ribavirin therapy for severe COVID-19: a retrospective cohort study. International Journal of Antimicrobial Agents 56: 106114. https://doi.org/10.1016/j.ijantimicag.2020.106114
  • te Velthuis AJW (2014) Common and unique features of viral RNA-dependent polymerases. Cellular and molecular life sciences: CMLS 71: 4403–4420. https://doi.org/10.1007/s00018-014-1695-z
  • Warren TK, Jordan R, Lo MK, Ray AS, Mackman RL, Soloveva V, Siegel D, Perron M, Bannister R, Hui HC, Larson N, Strickley R, Wells J, Stuthman KS, Van Tongeren SA, Garza NL, Donnelly G, Shurtleff AC, Retterer CJ, Gharaibeh D, Zamani R, Kenny T, Eaton BP, Grimes E, Welch LS, Gomba L, Wilhelmsen CL, Nichols DK, Nuss JE, Nagle ER, Kugelman JR, Palacios G, Doerffler E, Neville S, Carra E, Clarke MO, Zhang L, Lew W, Ross B, Wang Q, Chun K, Wolfe L, Babusis D, Park Y, Stray KM, Trancheva I, Feng JY, Barauskas O, Xu Y, Wong P, Braun MR, Flint M, McMullan LK, Chen S-S, Fearns R, Swaminathan S, Mayers DL, Spiropoulou CF, Lee WA, Nichol ST, Cihlar T, Bavari S (2016) Therapeutic efficacy of the small molecule GS-5734 against Ebola virus in rhesus monkeys. Nature 531: 381–385. https://doi.org/10.1038/nature17180
  • Xu Y, Barauskas O, Kim C, Babusis D, Murakami E, Kornyeyev D, Lee G, Stepan G, Perron M, Bannister R, Schultz BE, Sakowicz R, Porter D, Cihlar T, Feng JY (2021) Off-Target In Vitro Profiling Demonstrates that Remdesivir Is a Highly Selective Antiviral Agent. Antimicrobial Agents and Chemotherapy 65: e02237-20. https://doi.org/10.1128/AAC.02237-20
  • Zeuzem S, Dusheiko GM, Salupere R, Mangia A, Flisiak R, Hyland RH, Illeperuma A, Svarovskaia E, Brainard DM, Symonds WT, Subramanian GM, McHutchison JG, Weiland O, Reesink HW, Ferenci P, Hézode C, Esteban R (2014) Sofosbuvir and ribavirin in HCV genotypes 2 and 3. The New England Journal of Medicine 370: 1993–2001. https://doi.org/10.1056/NEJMoa1316145