Potent, highly selective, and non-thiol inhibitors of protein geranylgeranyltransferase-I.

摘要: The design, synthesis, and biological evaluation of a family peptidomimetic inhibitors protein geranylgeranyltransferase-I (PGGTase-I) are reported. based on the C-terminal CAAL sequence many geranylgeranylated proteins. Using 2-aryl-4-aminobenzoic acid derivatives as mimetics for central dipeptide (AA), we have attached series imidazole pyridine to N-terminus cysteine replacements. These non-thiol-containing peptidomimetics show exceptional selectivity PGGTase-I over closely related enzyme farnesyltransferase (PFTase). This is retained in whole cells where were shown block geranylgeranylation Rap-1A without affecting farnesylation small GTP-binding proteins such Ras.