Structure-based design, synthesis, and biological evaluation of irreversible human rhinovirus 3C protease inhibitors. 3. Structure - Activity studiesof ketomethylene-containing peptidomimetics

The structure-based design, chemical synthesis, and biological evaluation o f various ketomethylene-containing human rhinovirus (HRV) 3C protease (3CP) inhibitors are described. These compounds are comprised of a peptidomimeti c binding determinant and an ethyl propenoate Michael acceptor moiety which forms an irreversible covalent adduct with the active site cysteine residu e of the 30 enzyme. The ketomethylene-containing inhibitors typically displ ay slightly reduced 3CP inhibition activity relative to the corresponding p eptide-derived molecules, but they also exhibit significantly improved anti viral properties. Optimization of the ketomethylene-containing compounds is shown to provide several highly active 3C protease inhibitors which functi on as potent antirhinoviral agents (EC90 = < 1 mu M) against multiple virus serotypes in cell culture.