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Light-switched inhibitors of protein tyrosine phosphatase PTP1B based on phosphonocarbonyl phenylalanine as photoactive phosphotyrosine mimetic

Item Type:Article
Title:Light-switched inhibitors of protein tyrosine phosphatase PTP1B based on phosphonocarbonyl phenylalanine as photoactive phosphotyrosine mimetic
Creators Name:Wagner, S. and Schütz, A. and Rademann, J.
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 50muM. 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).
Keywords:Protein Tyrosine Phosphatases, Enzyme Inhibitors, Phosphotyrosine Mimetics, Protein Phosphorylation, PTP1B
Source:Bioorganic and Medicinal Chemistry
ISSN:0968-0896
Publisher:Elsevier / Pergamon (U.K.)
Volume:23
Number:12
Page Range:2839-2847
Date:15 June 2015
Official Publication:https://doi.org/10.1016/j.bmc.2015.03.074
PubMed:View item in PubMed

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