Synthesis and Separation of a Diastereomeric Pair of Phosphonopeptide Inhibitors of the Cyclic AMP-Dependent Protein Kinase Catalytic Subunit

Article abstract of DOI:10.1016/S0040-4020(01)85056-0

In this paper we report the establishment of a novel procedure to synthesize a nonhydrolyzable phosphonopeptide dead-end inhibitor of the catalytic subunit of cAMP-dependent protein kinase.This procedure has been optimized to maximize the peptide yield and gives a diastereomeric pair of heptapeptides that can be separed on a C-18 reverse phase HPLC column.The two peptides have been characterized by NMR and the ability of these peptides to inhibit the reaction of the catalytic subunit of cAMP-dependent protein kinase.Peptide A has a dissociation constant of 9 micromolar, and is a 10-fold better inhibitor as compared to peptide B.On the basis of this 10-fold greater inhibition afforded by peptide A, this peptide is assigned the all L-form configuration.It is expected that this procedure can easily be adapted to synthesize a variety of different peptide inhibitors which involve a nonhydrolyzable phosphate on an amino acid.