PEPTIDE INHIBITORS OF CAMP-DEPENDENT PROTEIN-KINASE

Abstract

A major substrate specificity requirement of the cAMP-dependent protein kinase is for adjacent arginine residues in proximity to the phosphorylatable serine, typically arranged R-R-X-S-X. Accordingly, attempts have been made to exploit this specificity requirement to obtain peptide inhibitors. While arginylarginine and polyarginine act as inhibitors, neither was particularly potent on an arginine molar basis. The most potent of the first generation peptide inhibitors was a suicide substrate developed by Bramson et al. in which 3-nitro-2-pyridinesulfenyl (Npys) cysteine was incorporated in place of the Kemptide phosphorylatable serine, L-R-R-A-(Npys)C-L-G. This analog had a Ki of 40μM. The mo..