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, CongBao Kang, Julien Lescar, Francesca Blasco, Paul W. Smith, and Pei-Yong Shi J. Virol. JVI.00855-15; Accepted manuscript posted online 27 May 2015, doi:10.1128/JVI.00855-15
The four serotypes of dengue virus (DENV-1 to -4) represent the most prevalent mosquito-borne viral pathogen 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 a 1.8¬ million compound library using a DENV-2 replicon assay. The compound selectively inhibits DENV-2 and -3 (EC5010-80 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 non-enzymatic transmembrane protein and a component of 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 that has good in vivo pharmacokinetics. Treatment of DENV-2-infected AG129 mice with compound¬ a suppressed viremia, even when the treatment started after viral infection. The results have proved 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.
TCR flagship “STOP Dengue” program from National Medical Research Council in Singapore to NITD