title: A combinatorial approach toward the generation of ambiphilic peptide-based inhibitors of protein:geranylgeranyl transferase-1.
abstract: A combinatorial synthesis of oligopeptide analogues and their evaluation as protein:geranylgeranyl transferase inhibitors is presented. The combinatorial strategy is based on the random mutation, in each new generation, of one of any of the four amino acid building blocks of which the most effective compounds of the previous generation are assembled. In this way, a progressive improvement of the average inhibitory activity was observed until the fifth generation. The most active inhibitors were found to inhibit PGGT-1 in the low micromolar range (IC(50): 3.8-8.1 microM).
authors.affiliation: Leiden Institute of Chemistry, Gorlaeus Laboratories, Leiden University, P.O. Box 9502, 2300 RA 2300 RA Leiden, The Netherlands.
authors.forename: Farid
authors.initials: F
authors.lastname: El Oualid
authors.forename: Hans
authors.initials: H
authors.lastname: van den Elst
authors.forename: Ingrid M
authors.initials: IM
authors.lastname: Leroy
authors.forename: Elsbeth
authors.initials: E
authors.lastname: Pieterman
authors.forename: Louis H
authors.initials: LH
authors.lastname: Cohen
authors.forename: Brigitte E A
authors.initials: BE
authors.lastname: Burm
authors.forename: Herman S
authors.initials: HS
authors.lastname: Overkleeft
authors.forename: Gijs A
authors.initials: GA
authors.lastname: van der Marel
authors.forename: Mark
authors.initials: M
authors.lastname: Overhand
mesh_terms: D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D000818:Animals; D002417:Cattle; D002853:Chromatography, Liquid; D020650:Combinatorial Chemistry Techniques / Q000379:methods*; D013058:Mass Spectrometry; D009842:Oligopeptides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D009842:Oligopeptides; D019883:Alkyl and Aryl Transferases; C083291:geranylgeranyltransferase type-I