title: The herpesvirus protease: mechanistic studies and discovery of inhibitors of the human cytomegalovirus protease.
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.
authors.affiliation: Searle Research and Development, Discovery Medicinal Chemistry, St. Louis, MO 63167, USA. DLFLYN@Monsanto.com
authors.forename: D L
authors.initials: DL
authors.lastname: Flynn
authors.forename: D P
authors.initials: DP
authors.lastname: Becker
authors.forename: V M
authors.initials: VM
authors.lastname: Dilworth
authors.forename: M K
authors.initials: MK
authors.lastname: Highkin
authors.forename: P J
authors.initials: PJ
authors.lastname: Hippenmeyer
authors.forename: K A
authors.initials: KA
authors.lastname: Houseman
authors.forename: L M
authors.initials: LM
authors.lastname: Levine
authors.forename: M
authors.initials: M
authors.lastname: Li
authors.forename: A E
authors.initials: AE
authors.lastname: Moormann
authors.forename: A
authors.initials: A
authors.lastname: Rankin
authors.forename: M V
authors.initials: MV
authors.lastname: Toth
authors.forename: C I
authors.initials: CI
authors.lastname: Villamil
authors.forename: A J
authors.initials: AJ
authors.lastname: Wittwer
authors.forename: B C
authors.initials: BC
authors.lastname: Holwerda
mesh_terms: D000998:Antiviral Agents / Q000737:chemistry / Q000494:pharmacology; D003587:Cytomegalovirus / Q000187:drug effects / Q000201:enzymology; D010450:Endopeptidases / Q000187:drug effects* / Q000235:genetics; D006564:Herpesviridae / Q000187:drug effects* / Q000201:enzymology*; D006801:Humans; D011480:Protease Inhibitors / Q000737:chemistry / Q000494:pharmacology; D012697:Serine Endopeptidases / Q000187:drug effects / Q000235:genetics
chemical_list: D000998:Antiviral Agents; D011480:Protease Inhibitors; D010450:Endopeptidases; D012697:Serine Endopeptidases