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The substrate specificity of SARS coronavirus 3C-like proteinase
Authors:Fan Keqiang  Ma Liang  Han Xiaofeng  Liang Huanhuan  Wei Ping  Liu Ying  Lai Luhua
Institution:State Key Laboratory of Structural Chemistry of Stable and Unstable Species, College of Chemistry, Peking University, Beijing 100871, China.
Abstract:The 3C-like proteinase of severe acute respiratory syndrome coronavirus (SARS) has been proposed to be a key target for structural based drug design against SARS. We have designed and synthesized 34 peptide substrates and determined their hydrolysis activities. The conserved core sequence of the native cleavage site is optimized for high hydrolysis activity. Residues at position P4, P3, and P3' are critical for substrate recognition and binding, and increment of beta-sheet conformation tendency is also helpful. A comparative molecular field analysis (CoMFA) model was constructed. Based on the mutation data and CoMFA model, a multiply mutated octapeptide S24 was designed for higher activity. The experimentally determined hydrolysis activity of S24 is the highest in all designed substrates and is close to that predicted by CoMFA. These results offer helpful information for the research on the mechanism of substrate recognition of coronavirus 3C-like proteinase.
Keywords:SARS  Coronavirus  3C-like proteinase  substrate specificity  CoMFA
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