title: Identification of covalent active site inhibitors of dengue virus protease.
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 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.
authors.affiliation: Experimental Therapeutics Centre, Agency for Science, Technology and Research (ASTAR), Singapore.
authors.forename: Xiaoying
authors.initials: X
authors.lastname: Koh-Stenta
authors.affiliation: Experimental Therapeutics Centre, Agency for Science, Technology and Research (ASTAR), Singapore.
authors.forename: Joma
authors.initials: J
authors.lastname: Joy
authors.affiliation: Experimental Therapeutics Centre, Agency for Science, Technology and Research (ASTAR), Singapore.
authors.forename: Si Fang
authors.initials: SF
authors.lastname: Wang
authors.affiliation: Experimental Therapeutics Centre, Agency for Science, Technology and Research (ASTAR), Singapore.
authors.forename: Perlyn Zekui
authors.initials: PZ
authors.lastname: Kwek
authors.affiliation: Experimental Therapeutics Centre, Agency for Science, Technology and Research (ASTAR), Singapore.
authors.forename: John Liang Kuan
authors.initials: JL
authors.lastname: Wee
authors.affiliation: Novartis Institute for Tropical Diseases, Singapore.
authors.forename: Kah Fei
authors.initials: KF
authors.lastname: Wan
authors.affiliation: Experimental Therapeutics Centre, Agency for Science, Technology and Research (ASTAR), Singapore.
authors.forename: Shovanlal
authors.initials: S
authors.lastname: Gayen
authors.affiliation: Experimental Therapeutics Centre, Agency for Science, Technology and Research (ASTAR), Singapore.
authors.forename: Angela Shuyi
authors.initials: AS
authors.lastname: Chen
authors.affiliation: Experimental Therapeutics Centre, Agency for Science, Technology and Research (ASTAR), Singapore.
authors.forename: CongBao
authors.initials: C
authors.lastname: Kang
authors.affiliation: Experimental Therapeutics Centre, Agency for Science, Technology and Research (ASTAR), Singapore.
authors.forename: May Ann
authors.initials: MA
authors.lastname: Lee
authors.affiliation: Experimental Therapeutics Centre, Agency for Science, Technology and Research (ASTAR), Singapore.
authors.forename: Anders
authors.initials: A
authors.lastname: Poulsen
authors.affiliation: Program in Emerging Infectious Diseases, Duke-NUS Graduate Medical School, Singapore.
authors.forename: Subhash G
authors.initials: SG
authors.lastname: Vasudevan
authors.affiliation: Experimental Therapeutics Centre, Agency for Science, Technology and Research (ASTAR), Singapore.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Hill
authors.affiliation: Experimental Therapeutics Centre, Agency for Science, Technology and Research (ASTAR), Singapore.
authors.forename: Kassoum
authors.initials: K
authors.lastname: Nacro
mesh_terms: D000998:Antiviral Agents / Q000737:chemistry / Q000494:pharmacology*; D020134:Catalytic Domain / Q000187:drug effects; D003716:Dengue Virus / Q000187:drug effects* / Q000201:enzymology*; D004305:Dose-Response Relationship, Drug; D009682:Magnetic Resonance Spectroscopy; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D015394:Molecular Structure; D011480:Protease Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D012697:Serine Endopeptidases / Q000378:metabolism*; D054852:Small Molecule Libraries / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000085242:Viral Proteases
chemical_list: D000998:Antiviral Agents; D011480:Protease Inhibitors; D012697:Serine Endopeptidases; D054852:Small Molecule Libraries; D017361:Viral Nonstructural Proteins; C080102:NS2B protein, flavivirus; C504449:NS3 protease, dengue virus; D000085242:Viral Proteases
keywords: active site binding; covalent inhibitor; flavivirus protease; pyrazole ester derivatives; small molecule optimization