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Potential and action mechanism of favipiravir as an antiviral against Junin virus

Favipiravir is a nucleoside analogue that inhibits the replication and transcription of a broad spectrum of RNA viruses, including pathogenic arenaviruses. In this study, we isolated a favipiravir-resistant mutant of Junin virus (JUNV), which is the causative agent of Argentine hemorrhagic fever, an...

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Autores principales: Zadeh, Vahid Rajabali, Afowowe, Tosin Oladipo, Abe, Haruka, Urata, Shuzo, Yasuda, Jiro
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9302769/
https://www.ncbi.nlm.nih.gov/pubmed/35816544
http://dx.doi.org/10.1371/journal.ppat.1010689
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author Zadeh, Vahid Rajabali
Afowowe, Tosin Oladipo
Abe, Haruka
Urata, Shuzo
Yasuda, Jiro
author_facet Zadeh, Vahid Rajabali
Afowowe, Tosin Oladipo
Abe, Haruka
Urata, Shuzo
Yasuda, Jiro
author_sort Zadeh, Vahid Rajabali
collection PubMed
description Favipiravir is a nucleoside analogue that inhibits the replication and transcription of a broad spectrum of RNA viruses, including pathogenic arenaviruses. In this study, we isolated a favipiravir-resistant mutant of Junin virus (JUNV), which is the causative agent of Argentine hemorrhagic fever, and analyzed the antiviral mechanism of favipiravir against JUNV. Two amino acid substitutions, N462D in the RNA-dependent RNA polymerase (RdRp) and A168T in the glycoprotein precursor GPC, were identified in the mutant. GPC-A168T substitution enhanced the efficiency of JUNV internalization, which explains the robust replication kinetics of the mutant in the virus growth analysis. Although RdRp-N462D substitution did not affect polymerase activity levels in a minigenome system, comparisons of RdRp error frequencies showed that the virus with RdRp-D462 possessed a significantly higher fidelity. Our next generation sequence (NGS) analysis showed a gradual accumulation of both mutations as we passaged the virus in presence of favipiravir. We also provided experimental evidence for the first time that favipiravir inhibited JUNV through the accumulation of transition mutations, confirming its role as a purine analogue against arenaviruses. Moreover, we showed that treatment with a combination of favipiravir and either ribavirin or remdesivir inhibited JUNV replication in a synergistic manner, blocking the generation of the drug-resistant mutant. Our findings provide new insights for the clinical management and treatment of Argentine hemorrhagic fever.
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spelling pubmed-93027692022-07-22 Potential and action mechanism of favipiravir as an antiviral against Junin virus Zadeh, Vahid Rajabali Afowowe, Tosin Oladipo Abe, Haruka Urata, Shuzo Yasuda, Jiro PLoS Pathog Research Article Favipiravir is a nucleoside analogue that inhibits the replication and transcription of a broad spectrum of RNA viruses, including pathogenic arenaviruses. In this study, we isolated a favipiravir-resistant mutant of Junin virus (JUNV), which is the causative agent of Argentine hemorrhagic fever, and analyzed the antiviral mechanism of favipiravir against JUNV. Two amino acid substitutions, N462D in the RNA-dependent RNA polymerase (RdRp) and A168T in the glycoprotein precursor GPC, were identified in the mutant. GPC-A168T substitution enhanced the efficiency of JUNV internalization, which explains the robust replication kinetics of the mutant in the virus growth analysis. Although RdRp-N462D substitution did not affect polymerase activity levels in a minigenome system, comparisons of RdRp error frequencies showed that the virus with RdRp-D462 possessed a significantly higher fidelity. Our next generation sequence (NGS) analysis showed a gradual accumulation of both mutations as we passaged the virus in presence of favipiravir. We also provided experimental evidence for the first time that favipiravir inhibited JUNV through the accumulation of transition mutations, confirming its role as a purine analogue against arenaviruses. Moreover, we showed that treatment with a combination of favipiravir and either ribavirin or remdesivir inhibited JUNV replication in a synergistic manner, blocking the generation of the drug-resistant mutant. Our findings provide new insights for the clinical management and treatment of Argentine hemorrhagic fever. Public Library of Science 2022-07-11 /pmc/articles/PMC9302769/ /pubmed/35816544 http://dx.doi.org/10.1371/journal.ppat.1010689 Text en © 2022 Zadeh et al https://creativecommons.org/licenses/by/4.0/This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Zadeh, Vahid Rajabali
Afowowe, Tosin Oladipo
Abe, Haruka
Urata, Shuzo
Yasuda, Jiro
Potential and action mechanism of favipiravir as an antiviral against Junin virus
title Potential and action mechanism of favipiravir as an antiviral against Junin virus
title_full Potential and action mechanism of favipiravir as an antiviral against Junin virus
title_fullStr Potential and action mechanism of favipiravir as an antiviral against Junin virus
title_full_unstemmed Potential and action mechanism of favipiravir as an antiviral against Junin virus
title_short Potential and action mechanism of favipiravir as an antiviral against Junin virus
title_sort potential and action mechanism of favipiravir as an antiviral against junin virus
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9302769/
https://www.ncbi.nlm.nih.gov/pubmed/35816544
http://dx.doi.org/10.1371/journal.ppat.1010689
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