Discovery of covalent prolyl oligopeptidase boronic ester inhibitors

Eur J Med Chem. 2020 Jan 1:185:111783. doi: 10.1016/j.ejmech.2019.111783. Epub 2019 Oct 18.

Abstract

Over the past decade, many drug discovery endeavors have been invested in targeting the serine proteases prolyl oligopeptidase (POP) for the treatment of Alzheimer's and Parkinson's disease and, more recently, epithelial cancers. Our research group has focused on the discovery of reversible covalent inhibitors, namely nitriles, to target the catalytic serine residue in this enzyme. While there have been many inhibitors discovered containing a nitrile to covalently bind to the catalytic serine, we have been investigating others, particularly boronic acids and boronic esters, the latter of which have been largely unexplored as covalent warheads. Herein we report a series of computationally-designed POP boronic ester pro-drug inhibitors exhibiting nanomolar-potencies in vitro as their active boronic acid species. These easily-accessible (1-2 step syntheses) compounds could facilitate future biochemical and biological studies of this enzyme's role in neurodegenerative diseases and cancer progression.

Keywords: Boronic ester; Covalent inhibitors; Peptidomimetic; Prolyl oligopeptidase inhibitors.

MeSH terms

  • Boronic Acids / chemical synthesis
  • Boronic Acids / chemistry
  • Boronic Acids / pharmacology*
  • Dose-Response Relationship, Drug
  • Drug Discovery*
  • Esters / chemical synthesis
  • Esters / chemistry
  • Esters / pharmacology*
  • Humans
  • Molecular Conformation
  • Molecular Docking Simulation
  • Prodrugs / chemical synthesis
  • Prodrugs / chemistry
  • Prodrugs / pharmacology*
  • Prolyl Oligopeptidases
  • Serine Endopeptidases / metabolism*
  • Structure-Activity Relationship

Substances

  • Boronic Acids
  • Esters
  • Prodrugs
  • Serine Endopeptidases
  • PREPL protein, human
  • Prolyl Oligopeptidases