RESUMO
Eleven analogues of the C-terminal Ca(1)a(2)X motif found in natural substrates of the prenyl transferases PFT and PGGT-1 were synthesized and evaluated for their inhibition potency and selectivity against PFT and PGGT-1. Replacement of the central dipeptide part a(1)a(2) by a benzylated sugar amino acid resulted in a good and highly selective PFT inhibitor (8, IC(50) = 250 +/- 20 nM). The methyl ester of 8 (13) selectively inhibited protein farnesylation in cultured cells.
Assuntos
Alquil e Aril Transferases/antagonistas & inibidores , Aminoácidos/síntese química , Açúcares Ácidos/síntese química , Alquil e Aril Transferases/química , Aminoácidos/química , Aminoácidos/farmacologia , Animais , Células CHO , Linhagem Celular , Cricetinae , Desenho de Fármacos , Farnesiltranstransferase , Relação Estrutura-Atividade , Açúcares Ácidos/química , Açúcares Ácidos/farmacologiaRESUMO
Ca(1)a(2)L analogues, having the central dipeptide a(1)a(2) replaced by a sugar amino acid, were provided at the N-terminal end directly or via a spacer with a lipid. The inhibitory potency toward PGGT-1 of the set of lipophilic Ca(1)a(2)L analogues was improved in comparison with the original analogues, 1 and 2. The most potent inhibitors, 39 and 40, were found to inhibit PGGT-1 with an IC(50)-value of 12.7 and 12.3 microM, respectively, which is a 6-fold improvement over the corresponding analogue 1.
Assuntos
Alquil e Aril Transferases/antagonistas & inibidores , Dipeptídeos/síntese química , Dipeptídeos/farmacologia , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Dipeptídeos/química , Inibidores Enzimáticos/química , Espectroscopia de Ressonância Magnética , Espectrometria de Massas , Especificidade por SubstratoRESUMO
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).