title: Benserazide, the first allosteric inhibitor of Coxsackievirus B3 3C protease.
abstract: Coxsackievirus B3 is the main cause of human viral myocarditis and cardiomyopathy. Virally encoded Coxsackievirus 3C protease (3C(pro)) plays an essential role in viral proliferation. Here, benserazide was discovered as a novel inhibitor from a drug library screen targeting Coxsackievirus 3C(pro) using a FRET-based enzyme assay. Benserazide, whose chemical structure has no electrophilic functional groups, was characterized as a non-competitive inhibitor by enzyme kinetic studies. A molecular docking study with benserazide and its analogs indicated that a novel putative allosteric binding site was involved. Specifically, a 2,3,4-trihydroxybenzyl moiety was determined to be a key pharmacophore for the enzyme's inhibitory activity. We suggest that the putative allosteric binding site may be a novel target for future therapeutic strategies.
authors.affiliation: School of Life Sciences, Gwangju Institute of Science and Technology, 123 Cheomdangwagi-ro, Buk-gu, Gwangju (GIST) 500-712, Republic of Korea.
authors.forename: Bo-Kyoung
authors.initials: BK
authors.lastname: Kim
authors.affiliation: New Drug Development Center (NDDC), Daegu-Gyeongbuk Medical Innovation Foundation (DGMIF), 80 Cheombok-ro, Dong-gu, Daegu 701-310, Republic of Korea.
authors.forename: Joong-Heui
authors.initials: JH
authors.lastname: Cho
authors.affiliation: Department of Medical System Engineering (DMSE), Gwangju Institute of Science and Technology (GIST), 123 Cheomdangwagi-ro, Buk-gu, Gwangju 500-712, Republic of Korea.
authors.forename: Pyeonghwa
authors.initials: P
authors.lastname: Jeong
authors.affiliation: School of Life Sciences, Steitz Center for Structural Biology, Systems Biology Research Center and Department of Chemistry, Gwangju Institute of Science and Technology (GIST), 123 Cheomdangwagi-ro, Buk-gu, Gwangju 500-712, Republic of Korea.
authors.forename: Youngjin
authors.initials: Y
authors.lastname: Lee
authors.affiliation: School of Life Sciences, Steitz Center for Structural Biology, Systems Biology Research Center and Department of Chemistry, Gwangju Institute of Science and Technology (GIST), 123 Cheomdangwagi-ro, Buk-gu, Gwangju 500-712, Republic of Korea.
authors.forename: Jia Jia
authors.initials: JJ
authors.lastname: Lim
authors.affiliation: School of Life Sciences, Steitz Center for Structural Biology, Systems Biology Research Center and Department of Chemistry, Gwangju Institute of Science and Technology (GIST), 123 Cheomdangwagi-ro, Buk-gu, Gwangju 500-712, Republic of Korea.
authors.forename: Kyoung Ryoung
authors.initials: KR
authors.lastname: Park
authors.affiliation: School of Life Sciences, Steitz Center for Structural Biology, Systems Biology Research Center and Department of Chemistry, Gwangju Institute of Science and Technology (GIST), 123 Cheomdangwagi-ro, Buk-gu, Gwangju 500-712, Republic of Korea.
authors.forename: Soo Hyun
authors.initials: SH
authors.lastname: Eom
authors.affiliation: School of Life Sciences, Gwangju Institute of Science and Technology, 123 Cheomdangwagi-ro, Buk-gu, Gwangju (GIST) 500-712, Republic of Korea; Department of Medical System Engineering (DMSE), Gwangju Institute of Science and Technology (GIST), 123 Cheomdangwagi-ro, Buk-gu, Gwangju 500-712, Republic of Korea. Electronic address: yongchul@gist.ac.kr.
authors.forename: Yong-Chul
authors.initials: YC
authors.lastname: Kim
mesh_terms: D000086042:3C Viral Proteases; D000495:Allosteric Site; D001545:Benserazide / Q000494:pharmacology*; D003546:Cysteine Endopeptidases / Q000235:genetics; D029822:Enterovirus B, Human / Q000201:enzymology*; D031541:Fluorescence Resonance Energy Transfer; D062105:Molecular Docking Simulation; D011480:Protease Inhibitors / Q000494:pharmacology*; D014764:Viral Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics
chemical_list: D011480:Protease Inhibitors; D014764:Viral Proteins; D001545:Benserazide; D003546:Cysteine Endopeptidases; D000086042:3C Viral Proteases
keywords: 3C protease; Allosteric binding site; Benserazide; Coxsackievirus B3; Enzyme kinetics; Non-competitive inhibitor