JMX0207, a Niclosamide Derivative with Improved Pharmacokinetics, Suppresses Zika Virus Infection Both In Vitro and In Vivo

Zhong Li, Jimin Xu, Yuekun Lang, Xiaoyu Fan, Lili Kuo, Lianna D'Brant, Saiyang Hu, Subodh Kumar Samrat, Nicole Trudeau, Anil M. Tharappel, Natasha Rugenstein, Cheri A. Koetzner, Jing Zhang, Haiying Chen, Laura D. Kramer, David Butler, Qing Yu Zhang, Jia Zhou, Hongmin Li

Research output: Contribution to journalArticlepeer-review

Abstract

Flaviviruses causes significant human disease. Recent outbreaks of the Zika virus highlight the need to develop effective therapies for this class of viruses. Previously we identified niclosamide as a broad-spectrum inhibitor for flaviviruses by targeting the interface between viral protease NS3 and its cofactor NS2B. Here, we screened a small library of niclosamide derivatives and identified a new analogue with improved pharmacokinetic properties. Compound JMX0207 showed improved efficacy in inhibition of the molecular interaction between NS3 and NS2B, better inhibition of viral protease function, and enhanced antiviral efficacy in the cell-based antiviral assay. The derivative also significantly reduced Zika virus infection on 3D mini-brain organoids derived from pluripotent neural stem cells. Intriguingly, the compound significantly reduced viremia in a Zika virus (ZIKV) animal model. In summary, a niclosamide derivative, JMX0207, was identified, which shows improved pharmacokinetics and efficacy against Zika virus both in vitro and in vivo.

Original languageEnglish (US)
Pages (from-to)2616-2628
Number of pages13
JournalACS Infectious Diseases
Volume6
Issue number10
DOIs
StatePublished - Oct 9 2020

Keywords

  • antiviral
  • Dengue virus
  • Flavivirus
  • protease inhibitor
  • Zika virus

ASJC Scopus subject areas

  • Infectious Diseases

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