Title

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

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

Comments

Author Posting © Informa HealthCare, 1997. This is the author's version of the work. It is posted here by permission of Informa Healthcare for personal use, not for redistribution. The definitive version was published in Drugs, Design, and Discovery, Volume 15, Issue 1, May, 1997.

Creative Commons License

Creative Commons License
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 3.0 License.

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