A Combinatorial Approach toward the Generation of Ambiphilic Peptide-Based Inhibitors of Protein:Geranylgeranyl Transferase-1

• Published in: Journal of combinatorial chemistry Vol. 7; no. 5; pp. 703 - 713
• Main Authors: El Oualid, Farid, van den Elst, Hans, Leroy, Ingrid M, Pieterman, Elsbeth, Cohen, Louis H, Burm, Brigitte E. A, Overkleeft, Herman S, van der Marel, Gijs A, Overhand, Mark
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 01.09.2005; Amer Chemical Soc
• Subjects: Alkyl and Aryl Transferases - antagonists & inhibitors; Alkyl and Aryl Transferases - chemistry; Animals; Cattle; Chemistry; Chemistry, Applied; Chemistry, Medicinal; Chemistry, Multidisciplinary; Chromatography, Liquid; Combinatorial Chemistry Techniques - methods; Life Sciences & Biomedicine; Mass Spectrometry; Oligopeptides - chemical synthesis; Oligopeptides - chemistry; Oligopeptides - pharmacology; Pharmacology & Pharmacy; Physical Sciences; Science & Technology; Structure-Activity Relationship; GENETIC ALGORITHMS; IN-VITRO; K-RAS; SOLID-PHASE SYNTHESIS; N-RAS; PRENYLTRANSFERASE INHIBITORS; BIOLOGICAL EVALUATION; FARNESYL; FARNESYLTRANSFERASE; BONE-RESORPTION
• ISSN: 1520-4766; 1520-4774
• DOI: 10.1021/cc0500203

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 (IC50:  3.8−8.1 μM).