Discovery of potent anilide inhibitors against the severe acute respiratory syndrome 3CL protease.
A diversified library of peptide anilides was prepared, and their inhibition activities against the SARS-CoV 3CL protease were examined by a fluorogenic tetradecapeptide substrate. The most potent inhibitor is an anilide derived from 2-chloro-4-nitroaniline, l-phenylalanine and 4-(dimethylamino)benzoic acid. This anilide is a competitive inhibitor of the SARS-CoV 3CL protease with K(i) = 0.03 muM. The molecular docking experiment indicates that the P1 residue of this anilide inhibitor is distant from the nucleophilic SH of Cys145 in the active site.
Shie
Jiun-Jie
JJ
Department of Chemistry, National Taiwan University, Taipei, 106, Taiwan.
Fang
Jim-Min
JM
Kuo
Chih-Jung
CJ
Kuo
Tun-Hsun
TH
Liang
Po-Huang
PH
Huang
Hung-Jyun
HJ
Yang
Wen-Bin
WB
Lin
Chun-Hung
CH
Chen
Jiun-Ling
JL
Wu
Yin-Ta
YT
Wong
Chi-Huey
CH
D000813:Anilides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D000086782:Coronavirus 3C Proteases; D003546:Cysteine Endopeptidases; D010450:Endopeptidases / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism*; D007700:Kinetics; D008958:Models, Molecular; D011480:Protease Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011487:Protein Conformation; D045473:Severe acute respiratory syndrome-related coronavirus / Q000187:drug effects / Q000201:enzymology; D045169:Severe Acute Respiratory Syndrome / Q000188:drug therapy*; D013329:Structure-Activity Relationship; D014764:Viral Proteins / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism*
D000813:Anilides; D000998:Antiviral Agents; D011480:Protease Inhibitors; D014764:Viral Proteins; D010450:Endopeptidases; D003546:Cysteine Endopeptidases; D000086782:Coronavirus 3C Proteases