Identification of covalent active site inhibitors of dengue virus protease

• DOI: 10.2147/dddt.s94207
• Publication Date: 2015-12-11T00:36:39Z
• Authors: Xiaoying Koh-Stenta; Joma Joy; Si Fang Wang; Perlyn Kwek; John Wee; Kah Fei Wan; Shovanlal Gayen; Angela Chen; CongBao Kang; May Ann Lee; Anders Poulsen; Subhash Vasudevan; Jeffrey Hill; Kassoum Nacro
• Keywords: Identification

Abstract: Dengue virus (DENV) protease is an attractive target for drug development; however, no compounds have reached clinical development to date. In this study, we utilized a potent West Nile inhibitor of the pyrazole ester derivative class as chemical starting point DENV development. Compound potency and selectivity were improved through structure-guided small molecule optimization, protease-inhibitor binding interactions validated biophysically using nuclear magnetic resonance. Our work strongly suggests that inhibits flavivirus targeted covalent modification active site serine, contrary allosteric mechanism previously described. Keywords: protease, inhibitor, binding, derivatives A Letter Editor has been received published article.