Journal
DRUG DESIGN DEVELOPMENT AND THERAPY
Volume 9, Issue -, Pages 6389-6399Publisher
DOVE MEDICAL PRESS LTD
DOI: 10.2147/DDDT.S94207
Keywords
flavivirus protease; small molecule optimization; covalent inhibitor; active site binding; pyrazole ester derivatives
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Funding
- Agency for Science, Technology and Research (A*STAR), Singapore
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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 virus protease inhibitor of the pyrazole ester derivative class as a chemical starting point for DENV protease drug development. Compound potency and selectivity for DENV protease were improved through structure-guided small molecule optimization, and protease-inhibitor binding interactions were validated biophysically using nuclear magnetic resonance. Our work strongly suggests that this class of compounds inhibits flavivirus protease through targeted covalent modification of active site serine, contrary to an allosteric binding mechanism as previously described.
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