title: Application of bioinformatics in search for cleavable peptides of SARS-CoV M(pro) and chemical modification of octapeptides.
abstract: According to the "distorted key" theory as elaborated in a review article years ago (Chou, K.C.: Analytical Biochemistry, 1996, 233, 1-14), the knowledge of the cleavable peptides by SARS-CoV M(pro) (severe acute respiratory syndrome coronavirus main proteinase) can provide very useful insights on developing drugs against SARS. In view of this, the softwares, ZCURVE_CoV 1.0 and ZCURVE_CoV 2.0 (http://tubic.tju.edu.cn/sars/), developed recently for SARS-Coronavirus are used to analyze the 36 complete SARS-Coronavirus RNA sequences in the gene bank NCBI (http://www.ncbi.nlm.nih.gov/) from different sources for protein coding genes, and to search for the cleavage sites of SARS-CoV M(pro) in polyproteins pp1a and pp1ab. A total of 396 cleavage points are found in the 36 SARS-Coronavirus and 11 cleavable octapeptides abstracted from the 396 cleavage sites. The statistical distributions of amino acids for the cleavable octapeptides at the subsites R4, R3, R2, R1, R1', R2', R3' and R4' are calculated. The cleavage-specific positions are on R2, R1 and R1', and the positions R3 and R4 are featured by some certain specificity for SARS-CoV M(pro). The structural characters of amino acid residues around the cleavage-specific positions are discussed. Two most promising octapeptides, i.e., NH(2)-ATLQ downward arrowAIAS-COOH and NH(2)-ATLQ downward arrowAENV-COOH, are selected to be the candidates for chemical modification, converting into the inhibitors of SARS-CoV M(pro). A possible strategy to convert a cleavable octapeptide by SARS enzyme into a drug candidate against SARS is elucidated.
authors.affiliation: Tianjin Normal University, Tianjin Institute of Bioinformatics and Drug Discovery, Tianjin, 300074, China.
authors.forename: Qishi
authors.initials: Q
authors.lastname: Du
authors.forename: Shuqing
authors.initials: S
authors.lastname: Wang
authors.forename: Zhiqin
authors.initials: Z
authors.lastname: Jiang
authors.forename: Weina
authors.initials: W
authors.lastname: Gao
authors.forename: Yun
authors.initials: Y
authors.lastname: Li
authors.forename: Dongqing
authors.initials: D
authors.lastname: Wei
authors.forename: Kuo-Chen
authors.initials: KC
authors.lastname: Chou
mesh_terms: D000595:Amino Acid Sequence; D000998:Antiviral Agents / Q000737:chemistry* / Q000494:pharmacology; D019295:Computational Biology; D000086782:Coronavirus 3C Proteases; D003546:Cysteine Endopeptidases / Q000737:chemistry* / Q000235:genetics; D015853:Cysteine Proteinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D015195:Drug Design; D016679:Genome, Viral; D008969:Molecular Sequence Data; D009842:Oligopeptides / Q000737:chemistry* / Q000235:genetics / Q000494:pharmacology; D045473:Severe acute respiratory syndrome-related coronavirus / Q000187:drug effects / Q000201:enzymology / Q000235:genetics; D020539:Sequence Analysis, Protein; D017423:Sequence Analysis, RNA; D012984:Software; D014764:Viral Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000235:genetics
chemical_list: D000998:Antiviral Agents; D015853:Cysteine Proteinase Inhibitors; D009842:Oligopeptides; D014764:Viral Proteins; D003546:Cysteine Endopeptidases; D000086782:Coronavirus 3C Proteases