title: Structure-based design of a parallel synthetic array directed toward the discovery of irreversible inhibitors of human rhinovirus 3C protease.
abstract: 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.
authors: Pfizer Global R&D-La Jolla/Agouron Pharmaceuticals, Inc., 10770 Science Center Road, San Diego, CA 92121, USA. tjohnson@agouron.com
authors: Theodore O
authors: TO
authors: Johnson
authors: Ye
authors: Y
authors: Hua
authors: Hiep T
authors: HT
authors: Luu
authors: Edward L
authors: EL
authors: Brown
authors: Fora
authors: F
authors: Chan
authors: Shao Song
authors: SS
authors: Chu
authors: Peter S
authors: PS
authors: Dragovich
authors: Brian W
authors: BW
authors: Eastman
authors: Rose Ann
authors: RA
authors: Ferre
authors: Shella A
authors: SA
authors: Fuhrman
authors: Thomas F
authors: TF
authors: Hendrickson
authors: Fausto C
authors: FC
authors: Maldonado
authors: David A
authors: DA
authors: Matthews
authors: James W
authors: JW
authors: Meador
authors: Amy K
authors: AK
authors: Patick
authors: Siegfried H
authors: SH
authors: Reich
authors: Donald J
authors: DJ
authors: Skalitzky
authors: Stephen T
authors: ST
authors: Worland
authors: Michelle
authors: M
authors: Yang
authors: Leora S
authors: LS
authors: Zalman
mesh_terms: D000086042:3C Viral Proteases; D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D020650:Combinatorial Chemistry Techniques; D018360:Crystallography, X-Ray; D003546:Cysteine Endopeptidases; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006367:HeLa Cells; D006801:Humans; D011485:Protein Binding; D012229:Rhinovirus / Q000737:chemistry / Q000187:drug effects*; D013329:Structure-Activity Relationship; D014764:Viral Proteins / Q000037:antagonists & inhibitors*
chemical_list: D000998:Antiviral Agents; D004791:Enzyme Inhibitors; D014764:Viral Proteins; D003546:Cysteine Endopeptidases; D000086042:3C Viral Proteases