Synthesis of phosphonomethyl-phenylalanine and phosphotyrosine containing cyclic peptides as inhibitors of protein tyrosine kinase/SH2 interactions.

Abstract

Linear and cyclic hexameric peptides were synthesized with the amino acid sequence Gly-Tyr-Val-Pro-Met-Leu, which corresponds to the autophosphorylation segment around Y751 of PDGF receptor β subunit. The natural L -tyrosine (position 2) was also substituted in peptide analogs with D -Tyr, L -tyrosine phosphate, and L - and D -4-phosphonomethyl-phenylalanine (Pmp). Fmoc chemistry-based SPPS methodology, and Rink resin support were used with diphenylphosphoryl azide as the cyclizing agent. The linear and cyclic peptides were characterized by circular dichroism spectroscopy. The peptides described were designed as inhibitors of receptor tyrosine kinase / src homology region 2 interactions that mediate mitogenic signal transduction pathways.