@article{PAR00012386,
  title = {{M}utations in the chikungunya virus non-structural proteins cause resistance to favipiravir ({T}-705), a broad-spectrum antiviral},
  author = {{D}elang, {L}. and {G}uerrero, {N}. {S}. and {T}as, {A}. and {Q}uerat, {G}. and {P}astorino, {B}. and {F}roeyen, {M}. and {D}allmeier, {K}. and {J}ochmans, {D}. and {H}erdewijn, {P}. and {B}ello, {F}. and {S}nijder, {E}. {J}. and de {L}amballerie, {X}avier and {M}artina, {B}. and {N}eyts, {J}. and van {H}emert, {M}. {J}. and {L}eyssen, {P}.},
  editor = {},
  language = {{ENG}},
  abstract = {{O}bjectives: {T}-705, also known as favipiravir, is a small-molecule inhibitor that is currently in clinical development for the treatment of influenza virus infections. {T}his molecule also inhibits the replication of a broad spectrum of other {RNA} viruses. {T}he 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. {M}ethods: {T}he 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. {T}he resistant phenotype was confirmed in cell culture and the whole genome was sequenced. {T}he identified mutations were reverse-engineered into an infectious clone to confirm their impact on the antiviral efficacy of favipiravir. {R}esults: {F}avipiravir inhibits the replication of laboratory strains and clinical isolates of {CHIKV}, as well as of a panel of other alphaviruses. {S}everal favipiravir-resistant {CHIKV} variants were independently selected and all of them in particular acquired the unique {K}291{R} mutation in the {RNA}-dependent {RNA} polymerase ({R}d{R}p). {R}everse-engineering of this {K}291{R} mutation into an infectious clone of {CHIKV} confirmed the link between the mutant genotype and the resistant phenotype. {I}nterestingly, this particular lysine is also highly conserved in the {R}d{R}p of positivestranded {RNA} viruses in general. {C}onclusions: {T}his study provides an important insight into the precise molecular mechanism by which favipiravir exerts its},
  keywords = {alphavirus ; polymerase ; ns{P}4},
  booktitle = {},
  journal = {{J}ournal of {A}ntimicrobial {C}hemotherapy},
  volume = {69},
  numero = {10},
  pages = {2770--2784},
  ISSN = {0305-7453},
  year = {2014},
  DOI = {10.1093/jac/dku209},
  URL = {https://www.documentation.ird.fr/hor/{PAR}00012386},
}