In:
Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 96, No. 20 ( 1999-09-28), p. 11000-11007
Abstract:
Human rhinoviruses, the most important etiologic agents of the
common cold, are messenger-active single-stranded monocistronic RNA viruses that have evolved a highly complex cascade of proteolytic
processing events to control viral gene expression and replication. Most maturation cleavages within the precursor polyprotein are mediated
by rhinovirus 3C protease (or its immediate precursor, 3CD), a cysteine protease with a trypsin-like polypeptide fold. High-resolution crystal
structures of the enzyme from three viral serotypes have been used for the design and elaboration of 3C protease inhibitors representing
different structural and chemical classes. Inhibitors having α,β-unsaturated carbonyl groups combined with peptidyl-binding
elements specific for 3C protease undergo a Michael reaction mediated by nucleophilic addition of the enzyme’s catalytic Cys-147, resulting
in covalent-bond formation and irreversible inactivation of the viral protease. Direct inhibition of 3C proteolytic activity in virally
infected cells treated with these compounds can be inferred from dose-dependent accumulations of viral precursor polyproteins as
determined by SDS/PAGE analysis of radiolabeled proteins. Cocrystal-structure-assisted optimization of 3C-protease-directed
Michael acceptors has yielded molecules having extremely rapid in vitro inactivation of the viral protease, potent
antiviral activity against multiple rhinovirus serotypes and low cellular toxicity. Recently, one compound in this series, AG7088, has
entered clinical trials.
Type of Medium:
Online Resource
ISSN:
0027-8424
,
1091-6490
DOI:
10.1073/pnas.96.20.11000
Language:
English
Publisher:
Proceedings of the National Academy of Sciences
Publication Date:
1999
detail.hit.zdb_id:
209104-5
detail.hit.zdb_id:
1461794-8
SSG:
11
SSG:
12
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