| Title | Structure-based design of a parallel synthetic array directed toward the discovery of irreversible inhibitors of human rhinovirus 3C protease. | ||
| Author | Johnson, Theodore O; Hua, Ye; Luu, Hiep T; Brown, Edward L; Chan, Fora; Chu, Shao Song; Dragovich, Peter S; Eastman, Brian W; Ferre, Rose Ann; Fuhrman, Shella A; Hendrickson, Thomas F; Maldonado, Fausto C; Matthews, David A; Meador, James W 3rd; Patick, Amy K; Reich, Siegfried H; Skalitzky, Donald J; Worland, Stephen T; Yang, Michelle; Zalman, Leora S | ||
| Journal | J Med Chem | Publication Year/Month | 2002-May |
| PMID | 11985469 | PMCID | -N/A- |
| Affiliation | 1.Pfizer Global R&D-La Jolla/Agouron Pharmaceuticals, Inc., 10770 Science Center Road, San Diego, CA 92121, USA. tjohnson@agouron.com. | ||
Utilizing the tools of parallel synthesis and structure-based design, a new class of Michael acceptor-containing, irreversible inhibitors of human rhinovirus 3C protease (HRV 3CP) was discovered. These inhibitors are shown to inhibit HRV-14 3CP with rates of inactivation ranging from 886 to 31 400 M(-1) sec(-1). These inhibitors exhibit antiviral activity when tested against HRV-14 infected H1-HeLa cells, with EC(50) values ranging from 1.94 to 0.15 microM. No cytotoxicity was observed at the limits of the assay concentration. A crystal structure of one of the more potent inhibitors covalently bound to HRV-2 3CP is detailed. These compounds were also tested against HRV serotypes other than type 14 and were found to have highly variable activities.