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 an important determinant for high affinity binding of peptides to PI 3-kinase p85 SH2 domains. In the present work, a series of linear and cyclic peptides based on the sequence "Gly-pTyr-Val-Pro-Met-Leu" as well as analogues having pTyr replaced by the phosphatase-resistant pTyr mimetics, phosphonomethyl phenylalanine (Pmp) or difluorophosphonomethyl phenylalanine (F(2)Pmp), were synthesized and their binding potency 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 Nle is a chemically more stable, isosteric Met homologue in which the sulfur has been replaced by a methylene.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-containing peptides, indicating that Met is not absolutely essential for high affinity binding to this SH2 domain.