Identification of covalent active site inhibitors of dengue virus protease
| Autor: | Kah Fei Wan, Xiaoying Koh-Stenta, Anders Poulsen, Joma Joy, Perlyn Zekui Kwek, John Liang Kuan Wee, May Ann Lee, Jeffrey Hill, Subhash G. Vasudevan, Shovanlal Gayen, Angela Shuyi Chen, Kassoum Nacro, CongBao Kang, Si Fang Wang |
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| Rok vydání: | 2015 |
| Předmět: |
Models
Molecular Magnetic Resonance Spectroscopy viruses medicine.medical_treatment Allosteric regulation Pharmaceutical Science Microbial Sensitivity Tests Viral Nonstructural Proteins Dengue virus medicine.disease_cause Antiviral Agents Small Molecule Libraries Structure-Activity Relationship Catalytic Domain Drug Discovery medicine Structure–activity relationship Protease Inhibitors Protease inhibitor (pharmacology) Original Research Pharmacology Drug Design Development and Therapy Protease Dose-Response Relationship Drug Molecular Structure active site binding biology Serine Endopeptidases virus diseases Dengue Virus small molecule optimization flavivirus protease biology.organism_classification Small molecule Virology NS2-3 protease Flavivirus Biochemistry covalent inhibitor pyrazole ester derivatives |
| Zdroj: | Drug Design, Development and Therapy |
| ISSN: | 1177-8881 |
| Popis: | Xiaoying Koh-Stenta,1 Joma Joy,1 Si Fang Wang,1 Perlyn Zekui Kwek,1 John Liang Kuan Wee,1 Kah Fei Wan,2 Shovanlal Gayen,1 Angela Shuyi Chen,1 CongBao Kang,1 May Ann Lee,1 Anders Poulsen,1 Subhash G Vasudevan,3 Jeffrey Hill,1 Kassoum Nacro11Experimental Therapeutics Centre, Agency for Science, Technologyand Research (A*STAR), Singapore; 2Novartis Institute for Tropical Diseases, Singapore; 3Program in Emerging Infectious Diseases, Duke-NUS Graduate Medical School, SingaporeAbstract: 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.Keywords: flavivirus protease, small molecule optimization, covalent inhibitor, active site binding, pyrazole ester derivativesA Letter to the Editor has been received and published for this article. |
| Databáze: | OpenAIRE |
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