An allosteric inhibitor of the Zika virus NS2B-NS3 protease with oral efficacy in mouse models
Abstract
Abstract The mosquito-transmitted Zika virus (ZIKV) poses a global health threat, with no approved antiviral drugs or vaccines currently available. Here, we report the discovery of a series of ZIKV NS3 protease inhibitors identified through phenotypic high-throughput screening (HTS) using a ZIKV replicon-based cellular assay, and the subsequent selection of resistant mutants. These inhibitors, characterized by the presence of an N -acylsydnone imine group, bind to a previously undescribed allosteric pocket of the protease, locking the enzyme into a catalytically inactive conformation. We describe the characterization of IRBM-Z-1, our initial allosteric hit and IRBM-Z-2, a potent inhibitor of ZIKV infectivity and other orthoflavivirus proteases with a favourable in vitro and in vivo ADME profile, resulting in oral efficacy against ZIKV infection in mouse models, with potential as a prophylactic agent for human use.
Article Details
Authors (30)
Jesus M. Ontoria
Esther Torrente
Antonino Missineo
Cristina Alli
Rita Graziani
Silvia Conti
Monica Bisbocci
Antonio Quotadamo
Federica Ferrigno
Alessandra Corio
Giovanni Ievoli
Leda Bencheva
Jérôme Amaudrut
Silvana Vasile
Elisa Beghetto
Chantal Paolini
Nadine Alaimo
Maria Veneziano
Martina Nibbio
Maria V. Orsale
Giulia Proto
Fabrizio Colaceci
Laura Orsatti
Vincenzo Pucci
Romano Di Fabio
Licia Tomei
Christian Montalbetti
Alberto Bresciani
Carlo Toniatti
Giacomo Paonessa