| Title | Structure-based design, synthesis, and biological evaluation of irreversible human rhinovirus 3C protease inhibitors. 3. Structure-activity studies of ketomethylene-containing peptidomimetics. | ||
| Author | Dragovich, P S; Prins, T J; Zhou, R; Fuhrman, S A; Patick, A K; Matthews, D A; Ford, C E; Meador, J W 3rd; Ferre, R A; Worland, S T | ||
| Journal | J Med Chem | Publication Year/Month | 1999-Apr |
| PMID | 10197964 | PMCID | -N/A- |
| Affiliation | 1.Agouron Pharmaceuticals, Inc., 3565 General Atomics Court, San Diego, California 92121, USA. | ||
The structure-based design, chemical synthesis, and biological evaluation of various ketomethylene-containing human rhinovirus (HRV) 3C protease (3CP) inhibitors are described. These compounds are comprised of a peptidomimetic binding determinant and an ethyl propenoate Michael acceptor moiety which forms an irreversible covalent adduct with the active site cysteine residue of the 3C enzyme. The ketomethylene-containing inhibitors typically display slightly reduced 3CP inhibition activity relative to the corresponding peptide-derived molecules, but they also exhibit significantly improved antiviral properties. Optimization of the ketomethylene-containing compounds is shown to provide several highly active 3C protease inhibitors which function as potent antirhinoviral agents (EC90 = <1 microM) against multiple virus serotypes in cell culture.