title: Peptidomimetic inhibitors of the human cytomegalovirus protease.
abstract: The development of peptidomimetic inhibitors of the human cytomegalovirus (HCMV) protease showing sub-micromolar potency in an enzymatic assay is described. Selective substitution of the amino acid residues of these inhibitors led to the identification of tripeptide inhibitors showing improvements in inhibitor potency of 27-fold relative to inhibitor 39 based upon the natural tetrapeptide sequence. Small side chains at P1 were well tolerated by this enzyme, a fact consistent with previous observations. The S2 binding pocket of HCMV protease was very permissive, tolerating lipophilic and basic residues. The substitutions tried at P3 indicated that a small increase in inhibitor potency could be realized by the substitution of a tert-leucine residue for valine. Substitutions of the N-terminal capping group did not significantly affect inhibitor potency. Pentafluoroethyl ketones, alpha,alpha-difluoro-beta-keto amides, phosphonates and alpha-keto amides were all effective substitutions for the activated carbonyl component and gave inhibitors which were selective for HCMV protease. A slight increase in potency was observed by lengthening the P1' residue of the alpha-keto amide series of inhibitors. This position also tolerated a variety of groups making this a potential site for future modifications which could modulate the physicochemical properties of these molecules.
authors.affiliation: Bio-Méga Research Division, Boehringer Ingelheim Ltd., Laval, Québec, Canada.
authors.forename: W
authors.initials: W
authors.lastname: Ogilvie
authors.forename: M
authors.initials: M
authors.lastname: Bailey
authors.forename: M A
authors.initials: MA
authors.lastname: Poupart
authors.forename: A
authors.initials: A
authors.lastname: Abraham
authors.forename: A
authors.initials: A
authors.lastname: Bhavsar
authors.forename: P
authors.initials: P
authors.lastname: Bonneau
authors.forename: J
authors.initials: J
authors.lastname: Bordeleau
authors.forename: Y
authors.initials: Y
authors.lastname: Bousquet
authors.forename: C
authors.initials: C
authors.lastname: Chabot
authors.forename: J S
authors.initials: JS
authors.lastname: Duceppe
authors.forename: G
authors.initials: G
authors.lastname: Fazal
authors.forename: S
authors.initials: S
authors.lastname: Goulet
authors.forename: C
authors.initials: C
authors.lastname: Grand-Maître
authors.forename: I
authors.initials: I
authors.lastname: Guse
authors.forename: T
authors.initials: T
authors.lastname: Halmos
authors.forename: P
authors.initials: P
authors.lastname: Lavallée
authors.forename: M
authors.initials: M
authors.lastname: Leach
authors.forename: E
authors.initials: E
authors.lastname: Malenfant
authors.forename: J
authors.initials: J
authors.lastname: O'Meara
authors.forename: R
authors.initials: R
authors.lastname: Plante
authors.forename: C
authors.initials: C
authors.lastname: Plouffe
authors.forename: M
authors.initials: M
authors.lastname: Poirier
authors.forename: F
authors.initials: F
authors.lastname: Soucy
authors.forename: C
authors.initials: C
authors.lastname: Yoakim
authors.forename: R
authors.initials: R
authors.lastname: Déziel
mesh_terms: D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D003587:Cytomegalovirus / Q000187:drug effects* / Q000201:enzymology; D006801:Humans; D011480:Protease Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D000998:Antiviral Agents; D011480:Protease Inhibitors