The viral capping enzyme nsP1: a novel target for the inhibition of chikungunya virus infection

摘要

The chikungunya virus (CHIKV) has become a substantial global health threat due to its massive reemergence,\udthe considerable disease burden and the lack of vaccines or therapeutics. We discovered a\udnovel class of small molecules ([1,2,3]triazolo[4,5-d]pyrimidin-7(6H)-ones) with potent in vitro activity\udagainst CHIKV isolates from different geographical regions. Drug-resistant variants were selected\udand these carried a P34S substitution in non-structural protein 1 (nsP1), the main enzyme involved in\udalphavirus RNA capping. Biochemical assays using nsP1 of the related Venezuelan equine encephalitis\udvirus revealed that the compounds specifically inhibit the guanylylation of nsP1. This is, to the best of\udour knowledge, the first report demonstrating that the alphavirus capping machinery is an excellent\udantiviral drug target. Considering the lack of options to treat CHIKV infections, this series of compounds\udwith their unique (alphavirus-specific) target offers promise for the development of therapy for CHIKV\udinfections.