Discovery of Mechanism-Based Inactivators for Human Pancreatic Carboxypeptidase A from a Focused Synthetic Library

Sebastián A. Testero, Carla Granados, Daniel Fernández, Pablo Gallego, Giovanni Covaleda, David Reverter, Josep Vendrell, Francesc X. Avilés, Irantzu Pallarès, Shahriar Mobashery

Research output: Contribution to journalArticleResearchpeer-review

3 Citations (Scopus)

Abstract

© 2017 American Chemical Society. Metallocarboxypeptidases (MCPs) are involved in many biological processes such as fibrinolysis or inflammation, development, Alzheimer's disease, and various types of cancer. We describe the synthesis and kinetic characterization of a focused library of 22 thiirane- and oxirane-based potential mechanism-based inhibitors, which led to discovery of an inhibitor for the human pro-carboxypeptidase A1. Our structural analyses show that the thiirane-based small-molecule inhibitor penetrates the barrier of the pro-domain to bind within the active site. This binding leads to a chemical reaction that covalently modifies the catalytic Glu270. These results highlight the importance of combined structural, biophysical, and biochemical evaluation of inhibitors in design strategies for the development of spectroscopically nonsilent probes as effective beacons for in vitro, in cellulo, and/or in vivo localization in clinical and industrial applications.
Original languageEnglish
Pages (from-to)1122-1127
JournalACS Medicinal Chemistry Letters
Volume8
Issue number10
DOIs
Publication statusPublished - 12 Oct 2017

Keywords

  • Carboxypeptidase A
  • X-ray crystallography
  • mechanism-based inactivators
  • thiiranes

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