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

  • ACS Infect Dis. 2020 Oct 9;6(10):2616-2628. doi: 10.1021/acsinfecdis.0c00217.
Zhong Li  1 ,  Jimin Xu  2 ,  Yuekun Lang  1 ,  Xiaoyu Fan  3 ,  Lili Kuo  1 ,  Lianna D'Brant  4 ,  Saiyang Hu  1 ,  Subodh Kumar Samrat  1 ,  Nicole Trudeau  4 ,  Anil M Tharappel  1 ,  Natasha Rugenstein  4 ,  Cheri A Koetzner  1 ,  Jing Zhang  1 ,  Haiying Chen  2 ,  Laura D Kramer  1  5 ,  David Butler  4 ,  Qing-Yu Zhang  3 ,  Jia Zhou  2 ,  Hongmin Li  1  5
Affiliations
  • 1. Wadsworth Center, New York State Department of Health, 120 New Scotland Avenue, Albany, New York 12208, United States.
  • 2. Chemical Biology Program, Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, Texas 77555, United States.
  • 3. Department of Pharmacology and Toxicology, College of Pharmacy, University of Arizona, Tucson, Arizona 85721, United States.
  • 4. The Neural Stem Cell Institute, 1 Discovery Drive, Rensselaer, New York 12144, United States.
  • 5. Department of Biomedical Sciences, School of Public Health, University at Albany, Albany, New York 12201, United States.
PMID: 32866370 DOI: 10.1021/acsinfecdis.0c00217
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.

Keywords
Dengue virus; Flavivirus; Zika virus; antiviral; protease inhibitor.
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