P1-lactam-containing inhibitors, particularly AG7088 (mean EC90 ~0.10 microM), displayed significantly increased human rhinovirus 3C protease inhibition compared to L-glutamine-derived molecules.
P1-lactam-containing inhibitors like AG7088 show potent antirhinoviral activity and selectivity, warranting further preclinical development.
The structure-based design, chemical synthesis, and biological evaluation of various human rhinovirus (HRV) 3C protease (3CP) inhibitors which incorporate P1 lactam moieties in lieu of an L-glutamine residue are described. These compounds are comprised of a tripeptidyl or 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 P1-lactam-containing inhibitors display significantly increased 3CP inhibition activity along with improved antirhinoviral properties relative to corresponding L-glutamine-derived molecules. In addition, several lactam-containing compounds exhibit excellent selectivity for HRV 3CP over several other serine and cysteine proteases and are not appreciably degraded by a variety of biological agents. One of the most potent inhibitors (AG7088, mean antirhinoviral EC90 approximately 0.10 microM, n = 46 serotypes) is shown to warrant additional preclinical development to explore its potential for use as an antirhinoviral agent.
Dragovich et al. (1999) studied Human rhinovirus (HRV) infection. P1-lactam-containing HRV 3C protease inhibitors (e.g., AG7088) vs. L-glutamine-derived molecules was evaluated on 3CP inhibition activity and antirhinoviral properties. P1-lactam-containing inhibitors, particularly AG7088 (mean EC90 ~0.10 microM), displayed significantly increased human rhinovirus 3C protease inhibition compared to L-glutamine-derived molecules.