title: Potent inhibition of insulin receptor dephosphorylation by a hexamer peptide containing the phosphotyrosyl mimetic F2Pmp.
abstract: Phosphonomethyl phenylalanine (Pmp) is a non-hydrolyzable phosphotyrosyl (pTyr) mimetic, which has been incorporated into eleven-mer Pmp-containing peptides that have previously been reported to competitively inhibit the protein-tyrosine phosphatases PTP1 and PTP 1B. We have recently shown that phosphonodifluoromethyl phenylalanine (F2Pmp) is superior to Pmp as a pTyr mimetic in SH2 domain-binding peptides. Herein we find using the hexameric peptide sequence Ac-D-A-D-E-X-L-amide, where X = (D/L)-Pmp or L-F2Pmp, that the half maximal inhibition values of these two peptides against PTP 1B-mediated dephosphorylation of autophosphorylated insulin receptor to be 200 microM and 100 nM, respectively. These data indicate that F2Pmp induces a three orders of magnitude enhancement in affinity relative to Pmp, resulting in an exceptionally potent peptide-based PTP inhibitor. We conclude that F2Pmp may be a generally useful tool in the preparation of selective, high affinity PTP inhibitors.
authors.affiliation: Laboratory of Medicinal Chemistry, NCI, National Institutes of Health, Bethesda, MD 20892.
authors.forename: T R
authors.initials: TR
authors.lastname: Burke
authors.forename: H K
authors.initials: HK
authors.lastname: Kole
authors.forename: P P
authors.initials: PP
authors.lastname: Roller
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D016466:CHO Cells; D002462:Cell Membrane / Q000378:metabolism; D006224:Cricetinae; D006801:Humans; D007202:Indicators and Reagents; D007700:Kinetics; D008969:Molecular Sequence Data; D009842:Oligopeptides / Q000138:chemical synthesis / Q000494:pharmacology*; D010649:Phenylalanine / Q000031:analogs & derivatives*; D019000:Phosphotyrosine; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism*; D011972:Receptor, Insulin / Q000037:antagonists & inhibitors*; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D014162:Transfection; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000378:metabolism
chemical_list: D007202:Indicators and Reagents; D009842:Oligopeptides; D011994:Recombinant Proteins; C089985:phosphonodifluoromethylphenylalanine; D019000:Phosphotyrosine; D014443:Tyrosine; D010649:Phenylalanine; D011972:Receptor, Insulin; D017027:Protein Tyrosine Phosphatases