NORLEUCINE AS A REPLACEMENT FOR METHIONINE IN PHOSPHATASE-RESISTANT LINEAR AND CYCLIC-PEPTIDES WHICH BIND TO P85 SH2 DOMAINS

A Met residue in the pTyr+3 position has previously been shown to be a n important determinant for high affinity binding of peptides to PI 3- kinase p85 SH2 domains. In the present work, a series of linear and cy clic peptides based on the sequence ''Gly-pTyr-Val-Pro-Met-Leu'' as we ll as analogues having pTyr replaced by the phosphatase-resistant pTyr mimetics, phosphonomethyl phenylalanine (Pmp) or difluorophosphonomet hyl phenylalanine (F(2)Pmp), were synthesized and their binding potenc y in p85 SH2 domain preparations compared with corresponding peptides in which the Met has been substituted by Nle. Nle is a chemically more stable, isosteric Met homologue in which the sulfur has been replaced by a methylene. Significant binding potency was retained by the Nle-c ontaining peptides, indicating that Met is not absolutely essential fo r high affinity binding to this SH2 domain.