.png){kind=icon}
.png){kind=icon}
Return
An allosteric inhibitor of the Zika virus NS2B-NS3 protease with oral efficacy in mouse models
.png){kind=icon}
OA
AI
DOI：10.1038/s41467-026-68943-x.png)
.png){kind=icon}
.png){kind=icon}
Share.png){kind=icon}
Save
Abstract
En 中文
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. The authors describe the discovery of a series of potent non-competitive allosteric inhibitors of the ZIKV NS2B-NS3 protease, which exhibit antiviral activity in vitro and robust oral efficacy against ZIKV infections in a mouse model.
Keywords:
Drug discovery and development
Target validation
X-ray crystallography
Science
Humanities and Social Sciences
multidisciplinary
AI Summary
Key information extracted from the uploaded paper, including a brief overview, abstract, background, key highlights, visual analysis, and future outlook.