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

Bioorg Med Chem. 2015 Jun 15;23(12):2839-47. doi: 10.1016/j.bmc.2015.03.074. Epub 2015 Apr 4.

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).

Keywords: Enzyme inhibitors; PTP1B; Phosphotyrosine mimetics; Photo-switchable inhibitors; Protein phosphorylation; Protein tyrosine phosphatases.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry*
  • Enzyme Inhibitors / pharmacology*
  • Humans
  • Light
  • Models, Molecular
  • Peptidomimetics / chemical synthesis
  • Peptidomimetics / chemistry*
  • Peptidomimetics / pharmacology*
  • Phosphotyrosine / analogs & derivatives*
  • Phosphotyrosine / chemical synthesis
  • Phosphotyrosine / pharmacology*
  • Protein Tyrosine Phosphatase, Non-Receptor Type 1 / antagonists & inhibitors*
  • Protein Tyrosine Phosphatase, Non-Receptor Type 1 / chemistry
  • Protein Tyrosine Phosphatase, Non-Receptor Type 1 / metabolism

Substances

  • Enzyme Inhibitors
  • Peptidomimetics
  • Phosphotyrosine
  • PTPN1 protein, human
  • Protein Tyrosine Phosphatase, Non-Receptor Type 1