Potent, highly selective, and non-thiol inhibitors of protein geranylgeranyltransferase-I |
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Authors: | Vasudevan A Qian Y Vogt A Blaskovich M A Ohkanda J Sebti S M Hamilton A D |
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Affiliation: | Department of Chemistry, Yale University, New Haven, Connecticut 06511, USA. |
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Abstract: | The design, synthesis, and biological evaluation of a family of peptidomimetic inhibitors of protein geranylgeranyltransferase-I (PGGTase-I) are reported. The inhibitors are based on the C-terminal CAAL sequence of many geranylgeranylated proteins. Using 2-aryl-4-aminobenzoic acid derivatives as mimetics for the central dipeptide (AA), we have attached a series of imidazole and pyridine derivatives to the N-terminus as cysteine replacements. These non-thiol-containing peptidomimetics show exceptional selectivity for PGGTase-I over the closely related enzyme protein farnesyltransferase (PFTase). This selectivity is retained in whole cells where the inhibitors were shown to block the geranylgeranylation of Rap-1A without affecting the farnesylation of small GTP-binding proteins such as Ras. |
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