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

The design, synthesis, and biological evaluation of a family of peptidomime tic inhibitors of protein geranylgeranyltransferase-I (PGGTase-I) are repor ted. The inhibitors are based on the C-terminal CAAL sequence of many geran ylgeranylated proteins. Using 2-aryl-4-aminobenzoic acid derivatives as mim etics for the central dipeptide (AA), we have attached a series of imidazol e and pyridine derivatives to the N-terminus as cysteine replacements. Thes e non-thiol-containing peptidomimetics show exceptional selectivity for PGG Tase-I over the closely related enzyme protein farnesyltransferase (PFTase) . This selectivity is retained in whole cells where the inhibitors were sho wn to block the geranylgeranylation of Rap-1A without affecting the farnesy lation of small GTP-binding proteins such as Ras.