title: Light-switched inhibitors of protein tyrosine phosphatase PTP1B based on phosphonocarbonyl phenylalanine as photoactive phosphotyrosine mimetic.
abstract: Phosphopeptide mimetics containing the 4-phosphonocarbonyl phenylalanine (pcF) as a photo-active phosphotyrosine isoster are developed as potent, light-switchable inhibitors of the protein tyrosine phosphatase PTP1B. The photo-active inhibitors 6-10 are derived from phosphopeptide substrates and are prepared from the suitably protected pcF building block 12 by Fmoc-based solid phase peptide synthesis. All pcF-containing peptides are moderate inhibitors of PTP1B with KI values between 10 and 50μM. Irradiation of the inhibitors at 365nm in the presence of the protein PTP1B amplify the inhibitory activity of pcF-peptides up to 120-fold, switching the KI values of the best inhibitors to the sub-micromolar range. Photo-activation of the inhibitors results in the formation of triplet intermediates of the benzoylphosphonate moiety, which deactivate PTP1B following an oxidative radical mechanism. Deactivation of PTP1B proceeds without covalent crosslinking of the protein target with the photo-switched inhibitors and can be reverted by subsequent addition of reducing agent dithiothreitol (DTT).
authors.affiliation: Freie Universität Berlin, Institute of Pharmacy, Medicinal Chemistry, Königin-Luise-Str. 2+4, 14195 Berlin, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Wagner
authors.affiliation: Max-Delbrück-Center for Molecular Medicine (MDC), Robert-Rössle-Str. 10, 13125 Berlin, Germany.
authors.forename: Anja
authors.initials: A
authors.lastname: Schütz
authors.affiliation: Freie Universität Berlin, Institute of Pharmacy, Medicinal Chemistry, Königin-Luise-Str. 2+4, 14195 Berlin, Germany. Electronic address: joerg.rademann@fu-berlin.de.
authors.forename: Jörg
authors.initials: J
authors.lastname: Rademann
mesh_terms: D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D008027:Light; D008958:Models, Molecular; D057786:Peptidomimetics / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D019000:Phosphotyrosine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology*; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1 / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D057786:Peptidomimetics; D019000:Phosphotyrosine; C516607:PTPN1 protein, human; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1
keywords: Enzyme inhibitors; PTP1B; Phosphotyrosine mimetics; Photo-switchable inhibitors; Protein phosphorylation; Protein tyrosine phosphatases