title: Protein-tyrosine phosphatase inhibition by a peptide containing the phosphotyrosyl mimetic, L-O-malonyltyrosine.
abstract: Peptides containing phosphonate based non-hydrolyzable phosphotyrosyl (pTyr) mimetics previously have been shown to be competitive inhibitors of protein-tyrosine phosphatases (PTPs). These agents suffer from low cellular penetration which is partially attributable to ionization of the phosphonate group at physiological pH. We have developed the non-phosphorus containing pTyr mimetic, L-O-malonyltyrosine (L-OMT) and herein demonstrate using a PTP 1B enzyme assay that it is superior to phosphonomethyl phenylalanine (Pmp) as a pTyr mimetic when incorporated into the hexamer peptide Ac-D-A-D-E-X-L-amide (X = D,L-Pmp, IC50 = 200 microM; X = L-OMT, IC50 = 10 microM). Prodrug protection of L-OMT as its carboxylic acid diester could potentially increase cellular penetration, thereby making this a valuable reagent for cellular studies.
authors.affiliation: Laboratory of Medicinal Chemistry, DCT, NCI, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: H K
authors.initials: HK
authors.lastname: Kole
authors.forename: M
authors.initials: M
authors.lastname: Akamatsu
authors.forename: B
authors.initials: B
authors.lastname: Ye
authors.forename: X
authors.initials: X
authors.lastname: Yan
authors.forename: D
authors.initials: D
authors.lastname: Barford
authors.forename: P P
authors.initials: PP
authors.lastname: Roller
authors.forename: T R
authors.initials: TR
authors.lastname: Burke
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D016466:CHO Cells; D006224:Cricetinae; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007700:Kinetics; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009842:Oligopeptides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D019000:Phosphotyrosine; D011487:Protein Conformation; D017027:Protein Tyrosine Phosphatases / Q000037:antagonists & inhibitors*; D011972:Receptor, Insulin / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000378:metabolism; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000302:isolation & purification; D014162:Transfection; D014443:Tyrosine / Q000031:analogs & derivatives*
chemical_list: D009842:Oligopeptides; D011994:Recombinant Proteins; C093257:malonyltyrosine; D019000:Phosphotyrosine; D014443:Tyrosine; D011972:Receptor, Insulin; D017027:Protein Tyrosine Phosphatases