Novel Class of Chikungunya Virus Small Molecule Inhibitors That Targets the Viral Capping Machinery
Rana Abdelnabi, Kristína Kováčiková, Julia Moesslacher, Kim Donckers, Verena Battisti, Pieter Leyssen, Thierry Langer, Gerhard Puerstinger, Gilles Quérat, Changqing Li, Étienne Decroly, Ali Taş, Arnaud Marchand, Patrick Chaltin, Bruno Coutard, Martijn J. van Hemert, Johan Neyts, Leen Delang
Abstract
Despite the worldwide reemergence of the chikungunya virus (CHIKV) and the high morbidity associated with CHIKV infections, there is no approved vaccine or antiviral treatment available. Here, we aimed to identify the target of a novel class of CHIKV inhibitors, i.e., the CHVB series. CHVB compounds inhibit the in vitro replication of CHIKV isolates with 50% effective concentrations in the low-micromolar range. A CHVB-resistant variant (CHVB res ) was selected that carried two mutations in the gene encoding nsP1 (responsible for viral RNA capping), one mutation in nsP2, and one mutation in nsP3.