| Abstract
| - The structure-based design, chemical synthesis, and biological evaluation of various humanrhinovirus (HRV) 3C protease (3CP) inhibitors which incorporate P1 lactam moieties in lieu ofan l-glutamine residue are described. These compounds are comprised of a tripeptidyl orpeptidomimetic binding determinant and an ethyl propenoate Michael acceptor moiety whichforms an irreversible covalent adduct with the active site cysteine residue of the 3C enzyme.The P1-lactam-containing inhibitors display significantly increased 3CP inhibition activity alongwith improved antirhinoviral properties relative to corresponding l-glutamine-derived molecules. In addition, several lactam-containing compounds exhibit excellent selectivity for HRV3CP over several other serine and cysteine proteases and are not appreciably degraded by avariety of biological agents. One of the most potent inhibitors (AG7088, mean antirhinoviralEC90 ≈ 0.10 μM, n = 46 serotypes) is shown to warrant additional preclinical development toexplore its potential for use as an antirhinoviral agent.
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