title: Quaternary structure, substrate selectivity and inhibitor design for SARS 3C-like proteinase.
abstract: The SARS coronavirus 3C-like proteinase is recognized as a potential drug design target for the treatment of severe acute respiratory syndrome. In the past few years, much work has been done to understand the catalytic mechanism of this target protein and to design its selective inhibitors. The protein exists as a dimer/monomer mixture in solution and the dimer was confirmed to be the active species for the enzyme reaction. Quantitative dissociation constants have been reported for the dimer by using analytic ultracentrifuge, gel filtration and enzyme assays. Though the enzyme is a cysteine protease with a chymotrypsin fold, SARS 3C-like proteinase follows the general base catalytic mechanism similar to chymotrypsin. As the enzyme can cut eleven different sites on the viral polyprotein, the substrate specificity has been studied by synthesized peptides corresponding or similar to the cleavage sites on the polyprotein. Predictive model was built for substrate structure and activity relationships and can be applied in inhibitor design. Due to the lack of potential drugs for the treatment of SARS, the discovery of inhibitors against SARS 3C-like proteinase, which can potentially be optimized as drugs appears to be highly desirable. Various groups have been working on inhibitor discovery by virtual screening, compound library screening, modification of existing compounds or natural products. High-throughput in vitro assays, auto-cleavage assays and viral replication assays have been developed for inhibition activity tests. Inhibitors with IC50 values as low as 60 nM have been reported.
authors.affiliation: State Key Laboratory for Structural Chemistry of Unstable and Stable Species, College of Chemistry and Molecular Engineering, Peking University, Beijing 100871, China. lhlai@pku.edu.cn
authors.forename: Luhua
authors.initials: L
authors.lastname: Lai
authors.forename: Xiaofeng
authors.initials: X
authors.lastname: Han
authors.forename: Hao
authors.initials: H
authors.lastname: Chen
authors.forename: Ping
authors.initials: P
authors.lastname: Wei
authors.forename: Changkang
authors.initials: C
authors.lastname: Huang
authors.forename: Shiyong
authors.initials: S
authors.lastname: Liu
authors.forename: Keqiang
authors.initials: K
authors.lastname: Fan
authors.forename: Lu
authors.initials: L
authors.lastname: Zhou
authors.forename: Zhenming
authors.initials: Z
authors.lastname: Liu
authors.forename: Jianfeng
authors.initials: J
authors.lastname: Pei
authors.forename: Ying
authors.initials: Y
authors.lastname: Liu
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000737:chemistry / Q000494:pharmacology*; D020134:Catalytic Domain; D017076:Computer-Aided Design; D000086782:Coronavirus 3C Proteases; D003546:Cysteine Endopeptidases / Q000737:chemistry*; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004353:Drug Evaluation, Preclinical / Q000379:methods; D006801:Humans; D008956:Models, Chemical; D011480:Protease Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D020836:Protein Structure, Quaternary; D045473:Severe acute respiratory syndrome-related coronavirus / Q000187:drug effects* / Q000201:enzymology; D013329:Structure-Activity Relationship; D013379:Substrate Specificity; D014764:Viral Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry*
chemical_list: D000998:Antiviral Agents; D011480:Protease Inhibitors; D014764:Viral Proteins; D003546:Cysteine Endopeptidases; D000086782:Coronavirus 3C Proteases