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.
Department of Chemistry, National Taiwan University, Taipei, 106, Taiwan.
Jiun-Jie
JJ
Shie
Jim-Min
JM
Fang
Chih-Jung
CJ
Kuo
Tun-Hsun
TH
Kuo
Po-Huang
PH
Liang
Hung-Jyun
HJ
Huang
Wen-Bin
WB
Yang
Chun-Hung
CH
Lin
Jiun-Ling
JL
Chen
Yin-Ta
YT
Wu
Chi-Huey
CH
Wong
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