The Herpesvirus Protease: Mechanistic Studies and Discovery of Inhibitors of the Human Cytomegalovirus Protease
Document Type
Article
Publication Date
5-1-1997
Publication Title
Drugs, Design, and Discovery
Volume
15
Issue
1
Pages
3-15
Publisher Name
Informa Healthcare
Abstract
The herpesvirus protease is a recently identified enzyme which is essential for viral replication. It is found in all herpesviruses and offers a new molecular target for therapeutic intervention. Its genomic structure has recently been described and consists of a large open reading frame which encodes a fusion protein containing an amino-terminal protease domain in-frame with a carboxyl-terminal "assembly protein-like" domain. Auto-processing releases the amino-terminal protease as a maturational enzyme. The herpesvirus protease has been characterized as a novel serine protease. Four surface accessible sulfhydryl groups have been identified in the human cytomegalovirus (HCMV) protease. Utilizing a fluorogenic DABCYL-EDANS substrate assay, directed screening has identified a class of sulfhydryl-modifying benzimidazolylmethyl sulfoxides which inhibits recombinant HCMV protease. Site-directed mutagenesis studies suggest oxidative modification of surface-accessible HCMV protease Cys138 (and possibly Cys161) by this class of inhibitors. The benzimidazolylmethyl sulfoxide 1 inhibits HCMV protease (IC50 = 1.9 microM), exhibits selectivity vs. mammalian serine proteases, and exhibits antiviral activity in an HCMV infected cell culture assay.
Identifier
PMID: 9332827
Recommended Citation
Flynn, Daniel L.; Becker, Daniel P.; Dilworth, Vickie; and Highkin, Maureen. The Herpesvirus Protease: Mechanistic Studies and Discovery of Inhibitors of the Human Cytomegalovirus Protease. Drugs, Design, and Discovery, 15, 1: 3-15, 1997. Retrieved from Loyola eCommons, Chemistry: Faculty Publications and Other Works,
Creative Commons License
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 3.0 License.
Copyright Statement
© 1997 Informa Healthcare
Comments
Author Posting © Informa HealthCare, 1997. The definitive version was published in Drugs, Design, and Discovery, Volume 15, Issue 1, May, 1997.