Protein-Tyrosine Phosphatase Inhibition by a Peptide Containing the Phosphotyrosyl Mimetic, L-O-Malonyltyrosine (L-OMT)

• Published in: Biochemical and biophysical research communications Vol. 209; no. 3; pp. 817 - 822
• Main Authors: Kole, H.K., Akamatsu, M., Ye, B., Yan, X.J., Barford, D., Roller, P.P., Burke, T.R.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 26.04.1995
• Subjects: Amino Acid Sequence; Animals; Binding Sites; CHO Cells; Cricetinae; Humans; Hydrogen-Ion Concentration; Kinetics; Models, Molecular; Molecular Sequence Data; Oligopeptides - chemical synthesis; Oligopeptides - chemistry; Oligopeptides - pharmacology; Phosphotyrosine; Protein Conformation; Protein Tyrosine Phosphatases - antagonists & inhibitors; Receptor, Insulin - antagonists & inhibitors; Receptor, Insulin - biosynthesis; Receptor, Insulin - metabolism; Recombinant Proteins - biosynthesis; Recombinant Proteins - isolation & purification; Transfection; Tyrosine - analogs & derivatives
• ISSN: 0006-291X; 1090-2104
• DOI: 10.1006/bbrc.1995.1573

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 μM; X = L-OMT, IC50 = 10 μM). Prodrug protection of L-OMT as its carboxylic acid diester could potentially increase cellular penetration, thereby making this a valuable reagent for cellular studies.