Mutations in the chikungunya virus non-structural proteins cause resistance to favipiravir (T-705), a broad-spectrum antiviral

T-705, also known as favipiravir, is a small-molecule inhibitor that is currently in clinical development for the treatment of influenza virus infections. This molecule also inhibits the replication of a broad spectrum of other RNA viruses. The objective of this study was to investigate the antivira...

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Bibliographic Details
Published in:Journal of antimicrobial chemotherapy 2014-10, Vol.69 (10), p.2770-2784
Main Authors: Delang, Leen, Segura Guerrero, Nidya, Tas, Ali, Quérat, Gilles, Pastorino, Boris, Froeyen, Mathy, Dallmeier, Kai, Jochmans, Dirk, Herdewijn, Piet, Bello, Felio, Snijder, Eric J, de Lamballerie, Xavier, Martina, Byron, Neyts, Johan, van Hemert, Martijn J, Leyssen, Pieter
Format: Article
Language:English
Subjects:
Amides - chemistry
Amides - pharmacology
Animals
Antiretroviral drugs
Antiviral Agents - chemistry
Antiviral Agents - pharmacology
Cell Line
Chikungunya Fever - drug therapy
Chikungunya Fever - virology
Chikungunya virus - drug effects
Chikungunya virus - genetics
Cytopathogenic Effect, Viral - drug effects
Disease Models, Animal
Dose-Response Relationship, Drug
Drug Resistance, Viral - genetics
Mice
Microbial Sensitivity Tests
Mutation
Phenotype
Proteins
Pyrazines - chemistry
Pyrazines - pharmacology
Reproducibility of Results
Viral Nonstructural Proteins - genetics
Virus Replication - drug effects
Viruses
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Summary:T-705, also known as favipiravir, is a small-molecule inhibitor that is currently in clinical development for the treatment of influenza virus infections. This molecule also inhibits the replication of a broad spectrum of other RNA viruses. The objective of this study was to investigate the antiviral effect of favipiravir on chikungunya virus (CHIKV) replication and to contribute to unravelling the molecular mechanism of action against this virus. The anti-CHIKV effect of favipiravir was examined in cell culture and in a mouse model of lethal infection. A five-step protocol was used to select for CHIKV variants with reduced susceptibility to favipiravir. The resistant phenotype was confirmed in cell culture and the whole genome was sequenced. The identified mutations were reverse-engineered into an infectious clone to confirm their impact on the antiviral efficacy of favipiravir. Favipiravir inhibits the replication of laboratory strains and clinical isolates of CHIKV, as well as of a panel of other alphaviruses. Several favipiravir-resistant CHIKV variants were independently selected and all of them in particular acquired the unique K291R mutation in the RNA-dependent RNA polymerase (RdRp). Reverse-engineering of this K291R mutation into an infectious clone of CHIKV confirmed the link between the mutant genotype and the resistant phenotype. Interestingly, this particular lysine is also highly conserved in the RdRp of positive-stranded RNA viruses in general. This study provides an important insight into the precise molecular mechanism by which favipiravir exerts its antiviral activity against (alpha)viruses, which may be of help in designing other potent broad-spectrum antivirals.
ISSN:0305-7453
1460-2091
DOI:10.1093/jac/dku209