The herpesvirus protease: mechanistic studies and discovery of inhibitors of the human cytomegalovirus protease

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 encod...

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Published inDrug design and discovery Vol. 15; no. 1; p. 3
Main Authors Flynn, D L, Becker, D P, Dilworth, V M, Highkin, M K, Hippenmeyer, P J, Houseman, K A, Levine, L M, Li, M, Moormann, A E, Rankin, A, Toth, M V, Villamil, C I, Wittwer, A J, Holwerda, B C
Format Journal Article
LanguageEnglish
Published Switzerland 01.05.1997
Subjects
Antiviral Agents - chemistry
Antiviral Agents - pharmacology
Cytomegalovirus - drug effects
Cytomegalovirus - enzymology
Endopeptidases - drug effects
Endopeptidases - genetics
Herpesviridae - drug effects
Herpesviridae - enzymology
Humans
Protease Inhibitors - chemistry
Protease Inhibitors - pharmacology
Serine Endopeptidases - drug effects
Serine Endopeptidases - genetics
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Summary: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.
ISSN:1055-9612