2. Academic Validation
  3. An allosteric inhibitor of the Zika virus NS2B-NS3 protease with oral efficacy in mouse models

An allosteric inhibitor of the Zika virus NS2B-NS3 protease with oral efficacy in mouse models

  • Nat Commun. 2026 Feb 10;17(1):1439. doi: 10.1038/s41467-026-68943-x.
Jesus M Ontoria 1,  Esther Torrente 2,  Antonino Missineo 3,  Cristina Alli 3,  Rita Graziani 3,  Silvia Conti 3,  Monica Bisbocci 3,  Antonio Quotadamo 2,  Federica Ferrigno 2,  Alessandra Corio 2,  Giovanni Ievoli 2,  Leda Bencheva 2 4,  Jérôme Amaudrut 2,  Silvana Vasile 2,  Elisa Beghetto 3,  Chantal Paolini 3,  Nadine Alaimo 3,  Maria Veneziano 2,  Martina Nibbio 2,  Maria V Orsale 2,  Giulia Proto 2,  Fabrizio Colaceci 2,  Laura Orsatti 2,  Vincenzo Pucci 2 5,  Romano Di Fabio 2 6,  Licia Tomei 3,  Christian Montalbetti 2,  Alberto Bresciani 3 7,  Carlo Toniatti 8,  Giacomo Paonessa 9
Affiliations

Affiliations

  • 1 Department of Drug Discovery, IRBM S.p.A., Pomezia, Italy. j.ontoria@irbm.com.
  • 2 Department of Drug Discovery, IRBM S.p.A., Pomezia, Italy.
  • 3 Department of Biology and Translational Research, IRBM S.p.A., Pomezia, Italy.
  • 4 Sibylla Biotech S.p.A., Bresso, Italy.
  • 5 Johnson & Johnson, Beerse, Belgium.
  • 6 Drug Discovery Unit, Vita Salute San Raffaele University, Milan, Italy.
  • 7 Tycho S.r.l., Bergamo, Italy.
  • 8 CSO, IRBM S.p.A., Pomezia, Italy.
  • 9 Department of Biology and Translational Research, IRBM S.p.A., Pomezia, Italy. g.paonessa@irbm.com.
PMID: 41667483 DOI: 10.1038/s41467-026-68943-x
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.

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