@article{PAR00009129,
  title = {{I}vermectin is a potent inhibitor of flavivirus replication specifically targeting {NS}3 helicase activity : new prospects for an old drug},
  author = {{M}astrangelo, {E}. and {P}ezzullo, {M}. and {D}e {B}urghgraeve, {T}. and {K}aptein, {S}. and {P}astorino, {B}. and {D}allmeier, {K}. and de {L}amballerie, {X}avier and {N}eyts, {J}. and {H}anson, {A}. {M}. and {F}rick, {D}. {N}. and {B}olognesi, {M}. and {M}ilani, {M}.},
  editor = {},
  language = {{ENG}},
  abstract = {{I}nfection with yellow fever virus ({YFV}), the prototypic mosquito-borne flavivirus, causes severe febrile disease with haemorrhage, multi-organ failure and a high mortality. {M}oreover, in recent years the {F}lavivirus genus has gained further attention due to re-emergence and increasing incidence of {W}est {N}ile, dengue and {J}apanese encephalitis viruses. {P}otent and safe antivirals are urgently needed. {S}tarting from the crystal structure of the {NS}3 helicase from {K}unjin virus (an {A}ustralian variant of {W}est {N}ile virus), we identified a novel, unexploited protein site that might be involved in the helicase catalytic cycle and could thus in principle be targeted for enzyme inhibition. {I}n silico docking of a library of small molecules allowed us to identify a few selected compounds with high predicted affinity for the new site. {T}heir activity against helicases from several flaviviruses was confirmed in in vitro helicase/enzymatic assays. {T}he effect on the in vitro replication of flaviviruses was then evaluated. {I}vermectin, a broadly used anti-helminthic drug, proved to be a highly potent inhibitor of {YFV} replication ({EC}50 values in the sub-nanomolar range). {M}oreover, ivermectin inhibited, although less efficiently, the replication of several other flaviviruses, i.e. dengue fever, {J}apanese encephalitis and tick-borne encephalitis viruses. {I}vermectin exerts its effect at a timepoint that coincides with the onset of intracellular viral {RNA} synthesis, as expected for a molecule that specifically targets the viral helicase. {T}he well-tolerated drug ivermectin may hold great potential for treatment of {YFV} infections. {F}urthermore, structure-based optimization may result in analogues exerting potent activity against flaviviruses other than {YFV}.},
  keywords = {antiviral drug discovery ; flavivirus helicase inhibition ; new use of existing drug ; in silico docking ; structure-based drug design},
  booktitle = {},
  journal = {{J}ournal of {A}ntimicrobial {C}hemotherapy},
  volume = {67},
  numero = {8},
  pages = {1884--1894},
  ISSN = {0305-7453},
  year = {2012},
  DOI = {10.1093/jac/dks147},
  URL = {https://www.documentation.ird.fr/hor/{PAR}00009129},
}