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Discovery of dengue virus NS4B inhibitors

Wang, Qingyin and Dong, Hongping and Zou, Bin and Karuna, Ratnaningrum and Wan, Kah Fei and Zou, Jing and Susila, Agatha and Yip, Jin Teen and Xu, Haoying and Ding, Mei and Chan, Wai Ling and Gu, Feng and Seah, Peck Gee and Liu, Wei and Lakshminarayana, Suresh Bangalore and Kang , Congbao and Julien, Lescar and Blasco, Francesca and Smith, Paul William and Shi, Pei-Yong (2015) Discovery of dengue virus NS4B inhibitors. Journal of Virology, 89 (16). pp. 8233-8244. ISSN 1098-5514

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.

Item Type: Article
Date Deposited: 29 Nov 2017 00:45
Last Modified: 25 Jan 2019 00:45
URI: https://oak.novartis.com/id/eprint/24618

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