Discovery of dengue virus NS4B inhibitors

Qing Yin Wang, Hongping Dong, Bin Zou, Ratna Karuna, Kah Fei Wan, Jing Zou, Agatha Susila, Andy Yip, Chao Shan, Kim Long Yeo, Haoying Xu, Mei Ding, Wai Ling Chan, Feng Gu, Peck Gee Seah, Wei Liu, Suresh B. Lakshminarayana, Cong Bao Kang, Julien Lescar, Francesca BlascoPaul W. Smith, Pei-Yong Shi

Research output: Contribution to journalArticle

45 Scopus citations

Abstract

The four serotypes of dengue virus (DENV-1 to -4) represent the most prevalent mosquito-borne viral pathogens in humans. No clinically approved vaccine or antiviral is currently available for DENV. Here we report a spiropyrazolopyridone compound that potently inhibits DENV both in vitro and in vivo. The inhibitor was identified through screening of a 1.8-million-compound library by using a DENV-2 replicon assay. The compound selectively inhibits DENV-2 and -3 (50% effective concentration [EC50], 10 to 80 nM) but not DENV-1 and -4 (EC50, > 20 μM). Resistance analysis showed that a mutation at amino acid 63 of DENV-2 NS4B (a nonenzymatic transmembrane protein and a component of the viral replication complex) could confer resistance to compound inhibition. Genetic studies demonstrate that variations at amino acid 63 of viral NS4B are responsible for the selective inhibition of DENV-2 and -3. Medicinal chemistry improved the physicochemical properties of the initial "hit" (compound 1), leading to compound 14a, which has good in vivo pharmacokinetics. Treatment of DENV-2-infected AG129 mice with compound 14a suppressed viremia, even when the treatment started after viral infection. The results have proven the concept that inhibitors of NS4B could potentially be developed for clinical treatment of DENV infection. Compound 14a represents a potential preclinical candidate for treatment of DENV-2- and -3-infected patients.

Original languageEnglish (US)
Pages (from-to)8233-8244
Number of pages12
JournalJournal of Virology
Volume89
Issue number16
DOIs
StatePublished - 2015
Externally publishedYes

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ASJC Scopus subject areas

  • Immunology
  • Virology

Cite this

Wang, Q. Y., Dong, H., Zou, B., Karuna, R., Wan, K. F., Zou, J., Susila, A., Yip, A., Shan, C., Yeo, K. L., Xu, H., Ding, M., Chan, W. L., Gu, F., Seah, P. G., Liu, W., Lakshminarayana, S. B., Kang, C. B., Lescar, J., ... Shi, P-Y. (2015). Discovery of dengue virus NS4B inhibitors. Journal of Virology, 89(16), 8233-8244. https://doi.org/10.1128/JVI.00855-15