title: Potent, highly selective, and non-thiol inhibitors of protein geranylgeranyltransferase-I.
abstract: The design, synthesis, and biological evaluation of a family of peptidomimetic inhibitors of protein geranylgeranyltransferase-I (PGGTase-I) are reported. The inhibitors are based on the C-terminal CAAL sequence of many geranylgeranylated proteins. Using 2-aryl-4-aminobenzoic acid derivatives as mimetics for the central dipeptide (AA), we have attached a series of imidazole and pyridine derivatives to the N-terminus as cysteine replacements. These non-thiol-containing peptidomimetics show exceptional selectivity for PGGTase-I over the closely related enzyme protein farnesyltransferase (PFTase). This selectivity is retained in whole cells where the inhibitors were shown to block the geranylgeranylation of Rap-1A without affecting the farnesylation of small GTP-binding proteins such as Ras.
authors.affiliation: Department of Chemistry, Yale University, New Haven, Connecticut 06511, USA.
authors.forename: A
authors.initials: A
authors.lastname: Vasudevan
authors.forename: Y
authors.initials: Y
authors.lastname: Qian
authors.forename: A
authors.initials: A
authors.lastname: Vogt
authors.forename: M A
authors.initials: MA
authors.lastname: Blaskovich
authors.forename: J
authors.initials: J
authors.lastname: Ohkanda
authors.forename: S M
authors.initials: SM
authors.lastname: Sebti
authors.forename: A D
authors.initials: AD
authors.lastname: Hamilton
mesh_terms: D016475:3T3 Cells; D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors*; D000818:Animals; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D019204:GTP-Binding Proteins / Q000096:biosynthesis; D007093:Imidazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D007930:Leucine / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051379:Mice; D018716:Molecular Mimicry; D017368:Protein Prenylation / Q000187:drug effects*; D013329:Structure-Activity Relationship; D020668:rap GTP-Binding Proteins
chemical_list: D004791:Enzyme Inhibitors; D007093:Imidazoles; D019883:Alkyl and Aryl Transferases; C083291:geranylgeranyltransferase type-I; C064911:p21(ras) farnesyl-protein transferase; D019204:GTP-Binding Proteins; D020668:rap GTP-Binding Proteins; D007930:Leucine