Inhibition of the severe acute respiratory syndrome 3CL protease by peptidomimetic α,β-unsaturated esters
Resource
Bioorganic & Medicinal Chemistry 13 (17): 5240-5252
Journal
Bioorganic and Medicinal Chemistry
Journal Volume
13
Journal Issue
17
Pages
5240-5252
Date Issued
2005
Author(s)
Shie, J.-J.
Kuo, T.-H.
Kuo, C.-J.
Liang, P.-H.
Huang, H.-J.
Wu, Y.-T.
Jan, J.-T.
Cheng, Y.-S.E.
Wong, C.-H.
Abstract
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.
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journal article
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