Structure-based design of a parallel synthetic array directed toward the discovery of irreversible inhibitors of human rhinovirus 3C protease.
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.
Johnson
Theodore O
TO
Pfizer Global R&D-La Jolla/Agouron Pharmaceuticals, Inc., 10770 Science Center Road, San Diego, CA 92121, USA. tjohnson@agouron.com
Hua
Ye
Y
Luu
Hiep T
HT
Brown
Edward L
EL
Chan
Fora
F
Chu
Shao Song
SS
Dragovich
Peter S
PS
Eastman
Brian W
BW
Ferre
Rose Ann
RA
Fuhrman
Shella A
SA
Hendrickson
Thomas F
TF
Maldonado
Fausto C
FC
Matthews
David A
DA
Meador
James W
JW
Patick
Amy K
AK
Reich
Siegfried H
SH
Skalitzky
Donald J
DJ
Worland
Stephen T
ST
Yang
Michelle
M
Zalman
Leora S
LS
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*
D000998:Antiviral Agents; D004791:Enzyme Inhibitors; D014764:Viral Proteins; D003546:Cysteine Endopeptidases; D000086042:3C Viral Proteases