Журнал микробиологии, эпидемиологии и иммунобиологии. 2021; 98: 213-220
Фавипиравир: скрытая опасность мутагенного действия
https://doi.org/10.36233/0372-9311-114Аннотация
Антивирусный химиопрепарат фавипиравир (ФП) имеет свойства функционального конкурента гуанозина и аденозина, в инфицированных клетках претерпевает химическую трансформацию ферментами клетки в нуклеотидную форму — ФП-рибозилтрифосфат, который способен связываться с вирусной РНК-зависимой РНК-полимеразой и встраиваться в цепочку вирусной РНК, вызывая заметное мутагенное действие посредством транзиций в геноме РНК-содержащих вирусов, преимущественно G→A и C→U. Усиление синтеза мутантных форм вирионов под действием ФП, помимо вирусингибирующего эффекта, несет угрозу появления новых опасных вирусных штаммов с повышенной патогенностью для человека и животных и приобретённой устойчивостью к химиопрепарату. Для минимизации мутагенного эффекта ФП возможны синтез новых модификаций ФП, лишенных способности встраиваться в молекулу синтезированной РНК; комбинированное применение ФП с противовирусными химиопрепаратами иного механизма действия и направленными на различные вирусные и/или клеточные мишени; курсовое применение при строгом врачебном контроле высоких терапевтических доз ФП для усиления летального мутагенного эффекта на инфекционный вирус в организме-реципиенте для предотвращения размножения его мутантных форм.
Список литературы
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Journal of microbiology, epidemiology and immunobiology. 2021; 98: 213-220
Favipiravir: the hidden threat of mutagenic action
Zhirnov O. P., Chernyshova A. I.
https://doi.org/10.36233/0372-9311-114Abstract
The antiviral drug favipiravir (FVP), which is a structural analogue of guanosine, undergoes chemical transformation in infected cells by cellular enzymes into a nucleotide form — favipiravir ribose triphosphate (FVPRTP). FVP-RTP is able to bind to viral RNA-dependent RNA polymerase and integrate into the viral RNA chain, causing a significant mutagenic effect through G→A and С→U transitions in the viral RNA genome. Besides the virus inhibiting effect, the increased synthesis of mutant virions under the action of FPV possess a threat of the emergence of novel threatening viral strains with high pathogenicity for humans and animals and acquired resistance to chemotherapeutic compound. There are three ways to minimize this mutagenic effect of FP. (1) Synthesis of new FPV modifications lacking the ability to integrate into the synthesized viral RNA molecule. (2) The combined use of FPV with antiviral chemotherapeutic drugs of a different mechanism of action directed at various viral and/or host cell targets. (3) Permanent application of high therapeutic doses of FPV under the strict medical control to enhance the lethal mutagenic effect on an infectious virus in the recipient organism to prevent the multiplication of its mutant forms.
References
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2. Tsai S.C., Lu C.C., Bau D.T., Chiu Y.J., Yen Y.T., Hsu Y.M., et al. Approaches towards fighting the COVID 19 pandemic (Review). Int. J. Mol. Med. 2020; 47(1): 3–22. https://doi.org/10.3892/ijmm.2020.4794
3. Furuta Y., Gowen B.B., Takahashi K., Shiraki K., Smee D.F., Barnard D.L. Favipiravir (T-705), a novel viral RNA polymerase inhibitor. Antiviral Res. 2013; 100(2): 446–54. https://doi.org/10.1016/j.antiviral.2013.09.015
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6. Shiraki K., Daikoku T. Favipiravir, an anti-influenza drug against life-threatening RNA virus infections. Pharmacol Ther. 2020; 209: 107512. https://doi.org/10.1016/j.pharmthera.2020.107512
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8. Abdelnabi R., Morais A.T.S., Leyssen P., Imbert I., Beaucourt S., Blanc H., et al. Understanding the Mechanism of the Broad-Spectrum Antiviral Activity of Favipiravir (T-705): Key Role of the F1 Motif of the Viral Polymerase. J. Virol. 2017; 91(12): e00487–17. https://doi.org/10.1128/jvi.00487-17
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16. Baranovich T., Wong S.S., Armstrong J., Marjuki H., Webby R.J., Webster R.G., et al. T-705 (favipiravir) induces lethal mutagenesis in influenza A H1N1 viruses in vitro. J. Virol. 2013; 87(7): 3741–51. https://doi.org/10.1128/jvi.02346-12
17. Arias A., Thorne L., Goodfellow I. Favipiravir elicit antiviral mutagenesis during virus replication in vivo. eLife. 2014; 3: e03679. https://doi.org/10.7554/elife.03679
18. Sangawa H., Komeno T., Nishikawa H., Yoshida A., Takahashi K., Nomura N., et al. Mechanism of action of T-705 ribosyl triphosphate against influenza virus RNA polymerase. Antimicrob. Agents Chemother. 2013; 57(11): 5202–8. https://doi.org/10.1128/aac.00649-13
19. Jin Z., Smith L.K., Rajwanshi V.K., Kim B., Deval J. The ambiguous base-pairing and high substrate efficiency of T-705 (Favipiravir) ribofuranosyl 5’-triphosphate towards influenza A virus polymerase. PLoS One. 2013; 8(7): e68347. https://doi.org/10.1371/journal.pone.0068347
20. de Ávila A.I., Gallego I., Soria M.E., Gregori J., Quer J., Esteban J.I., et al. Lethal mutagenesis of hepatitis C virus induced by Favipiravir. PLoS One. 2016; 11(10): e0164691. https://doi.org/10.1371/journal.pone.0164691
21. Guedj J., Piorkowski G., Jacquot F., Madelain V., Nguyen T.H.T., Rodallec A., et al. Antiviral efficacy of Favipiravir against Ebola virus: A translational study in cynomolgus macaques. PLoS Med. 2018; 15(3): e1002535. https://doi.org/10.1371/journal.pmed.1002535
22. Goldhill D.H., te Velthuis A.J.W., Fletcher R.A., Langat P., Zambon M., Lackenby A., et al. The mechanism of resistance to Favipiravir in influenza. Proc. Natl Acad. Sci. USA. 2018; 115(45): 11613–8. https://doi.org/10.1073/pnas.1811345115
23. Shannon A., Selisko B., Le N.T., Huchting J., Touret F., Piorkowski G., et al. Rapid incorporation of Favipiravir by the fast and permissive viral RNA polymerase complex results in SARS-CoV-2 lethal mutagenesis. Nat. Commun. 2020; 11(1): 4682. https://doi.org/10.1038/s41467-020-18463-z
24. Grande-Pérez A., Lazaro E., Lowenstein P., Domingo E., Manrubia S.C. Suppression of viral infectivity through lethal defection. Proc. Natl Acad. Sci. USA. 2005; 102(12): 4448–52. https://doi.org/10.1073/pnas.0408871102
25. Perales C., Mateo R., Mateu M.G., Domingo E. Insights into RNA virus mutant spectrum and lethal mutagenesis events: replicative interference and complementation by multiple point mutants. J. Mol. Biol. 2007; 369(4): 985–1000. https://doi.org/10.1016/j.jmb.2007.03.074
26. 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: 269–71. https://doi.org/10.1038/s41422-020-0282-0
27. Cai Q., Yang M., Liu D., Chen J., Shu D., Xia J., et al. Experimental treatment with Favipiravir for COVID-19: An open-label control study. Engineering (Beijing). 2020; 6(10): 1192–8. https://doi.org/10.1016/j.eng.2020.03.007
28. Joshi S., Parkar J., Ansari A., Vora A., Talwar D., Tiwaskar M., et al. Role of Favipiravir in the treatment of COVID-19. Int. J. Infect. Dis. 2020; 102: 501–8. https://doi.org/10.1016/j.ijid.2020.10.069
29. Ivashchenko A.A., Dmitriev K.A., Vostokova N.V., Azarova V.N., Blinow A.A., Egorova A.N., et al. AVIFAVIR for treatment of patients with moderate COVID-19: Interim results of a phase II/III multicenter randomized clinical trial. Clin. Infect. Dis. 2020; ciaa1176. https://doi.org/10.1093/cid/ciaa1176
30. Eloy P., Solas C., Touret F., Mentré F., Malvy D., de Lamballerie X., et al. Dose rationale for Favipiravir use in patients infected with SARS-CoV-2. Clin. Pharmacol. Ther. 2020; 108(2): 188. https://doi.org/10.1002/cpt.1877
31. Perales C., Gallego I., de ́Avila A.I., Soria M.E., Gregori J., Quer J., et al. The increasing impact of lethal mutagenesis of viruses. Future Med. Chem. 2019; 11(13): 1645–57. https://doi.org/10.4155/fmc-2018-0457
32. Li G., De Clercq E. Therapeutic options for the 2019 novel coronavirus (2019-nCoV). Nat. Rev. Drug Discov. 2020; 19(3): 149–50. https://doi.org/10.1038/d41573-020-00016-0
33. Ferron F. Structural and molecular basis of mismatch correction and ribavirin excision from coronavirus RNA. Proc. Natl. Acad. Sci. USA. 2018; 115(2): E162–71. https://doi.org/10.1073/pnas.1718806115
34. Ilyushina N.A., Bovin N.V., Webster R.G., Govorkova E.A. Combination chemotherapy, a potential strategy for reducing the emergence of drug-resistant influenza A variants. Antiviral Res. 2006; 70(3): 121–31. https://doi.org/10.1016/j.antiviral.2006.01.012
35. Lu Y., Hardes K., Dahms S.O., Böttcher-Friebertshäuser E., Steinmetzer T., Than M.E., et al. Peptidomimetic furin inhibitor MI-701 in combination with oseltamivir and ribavirin efficiently blocks propagation of highly pathogenic avian influenza viruses and delays high level oseltamivir resistance in MDCK cells. Antiviral Res. 2015; 120: 89–100. https://doi.org/10.1016/j.antiviral.2015.05.006
36. Baz M., Carbonneau J., Rhéaume C., Cavanagh M.H., Boivin G. Combination therapy with Oseltamivir and Favipiravir delays mortality but does not prevent Oseltamivir resistance in immunodeficient mice infected with pandemic A(H1N1) influenza virus. Viruses. 2018; 10(11): 610. https://doi.org/10.3390/v10110610
37. Beigel J.H., Bao Y., Beeler J., Manosuthi W., Slandzicki A., Dar S.M., et al. A randomized double-blind phase 2 study of combination antivirals for the treatment of influenza. Lancet Infect. Dis. 2017; 17: 1255–65. https://doi.org/10.1016/S1473-3099(17)30476-0
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