Discovery and Optimization of IRBM-Z-2, an Allosteric Zika Virus NS2B-NS3 Protease Inhibitor Exhibiting In Vivo Efficacy
Zika virus is an increasing medical and socio-economic burden in (sub)tropical regions, with no effective treatments available. Previously, we identified a novel series of N-carbamoylsydnone imine derivatives as potent ZIKV NS2B-NS3 protease inhibitors through phenotypic antiviral screening. Here, we report the optimization of this series, leading to IRBM-Z-2, a nanomolar inhibitor active in both biochemical and cellular assays, exhibiting no cytotoxicity. IRBM-Z-2 demonstrates favorable oral bioavailability, low clearance, and strong prophylactic efficacy in mouse models of ZIKV infection. These results highlight IRBM-Z-2 as a promising therapeutic candidate against ZIKV and a potential foundation for developing broad-spectrum orthoflavirus agents.
Authors
- Antonio Quotadamo (ORCID: https://orcid.org/0000-0002-0357-3504)
- Alessandra Corio (ORCID: https://orcid.org/0000-0002-3238-6687)
- Carlo Toniatti (ORCID: https://orcid.org/0000-0001-9493-344X)
- Esther Torrente (ORCID: https://orcid.org/0000-0002-3594-9334)
- Cristina Alli
- Giacomo Paonessa (ORCID: https://orcid.org/0000-0002-8552-5054)
- Federica Ferrigno (ORCID: https://orcid.org/0000-0002-0054-4345)
- Giulia Proto
- Maria Vittoria Orsale
- Monica Bisbocci
- Annalise Di Marco (ORCID: https://orcid.org/0000-0001-5211-6230)
- Rita Graziani
- Maria Veneziano
- Silvana Vasile (ORCID: https://orcid.org/0000-0001-5578-7996)
- Giovanni Ievoli
- Christian Montalbetti
- Jesus M. Ontoria
Institutions
- Istituto di Farmacologia Traslazionale (IT)
- IRBM Science Park (IT)
Publication Details
- Journal
- Journal of Medicinal Chemistry
- Published
- 2026-05-29
- DOI
- https://doi.org/10.1021/acs.jmedchem.6c00476
- Primary Topic
- Mosquito-borne diseases and control
- Type
- article
- Field-Weighted Citation Impact
- 0.00