Inhibition of the severe acute respiratory syndrome 3CL protease by peptidomimetic alpha,beta-unsaturated esters.
The proteolytic processing of polyproteins by the 3CL protease of severe acute respiratory syndrome coronavirus is essential for the viral propagation. A series of tripeptide alpha,beta-unsaturated esters and ketomethylene isosteres, including AG7088, are synthesized and assayed to target the 3CL protease. Though AG7088 is inactive (IC50 > 100 microM), the ketomethylene isosteres and tripeptide alpha,beta-unsaturated esters containing both P1 and P2 phenylalanine residues show modest inhibitory activity (IC50 = 11-39 microM). The Phe-Phe dipeptide inhibitors 18a-e are designed on the basis of computer modeling of the enzyme-inhibitor complex. The most potent inhibitor 18c with an inhibition constant of 0.52 microM is obtained by condensation of the Phe-Phe dipeptide alpha,beta-unsaturated ester with 4-(dimethylamino)cinnamic acid. The cell-based assays also indicate that 18c is a nontoxic anti-SARS agent with an EC50 value of 0.18 microM.
Department of Chemistry, National Taiwan University, Taipei 106, Taiwan.
Jiun-Jie
JJ
Shie
Jim-Min
JM
Fang
Tun-Hsun
TH
Kuo
Chih-Jung
CJ
Kuo
Po-Huang
PH
Liang
Hung-Jyun
HJ
Huang
Yin-Ta
YT
Wu
Jia-Tsrong
JT
Jan
Yih-Shyun E
YS
Cheng
Chi-Huey
CH
Wong
D000818:Animals; D015153:Blotting, Western; D002522:Chlorocebus aethiops; D003198:Computer Simulation; D000086782:Coronavirus 3C Proteases; D003546:Cysteine Endopeptidases; D010450:Endopeptidases / Q000737:chemistry; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D004952:Esters; D007555:Isoxazoles / Q000737:chemistry / Q000494:pharmacology*; D007700:Kinetics; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry / Q000379:methods; D008958:Models, Molecular; D018716:Molecular Mimicry; D010455:Peptides / Q000737:chemistry / Q000494:pharmacology*; D010649:Phenylalanine / Q000031:analogs & derivatives; D011760:Pyrrolidinones / Q000737:chemistry / Q000494:pharmacology*; D014633:Valine / Q000031:analogs & derivatives; D014709:Vero Cells; D014764:Viral Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry
D004791:Enzyme Inhibitors; D004952:Esters; D007555:Isoxazoles; D010455:Peptides; D011760:Pyrrolidinones; D014764:Viral Proteins; D010649:Phenylalanine; D010450:Endopeptidases; D003546:Cysteine Endopeptidases; D000086782:Coronavirus 3C Proteases; D014633:Valine; C118874:rupintrivir