Scholarlink

<p>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 <i>N</i>-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.</p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

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

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年2月10日

查看全文
  • 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

摘要

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.