Targeted covalent inhibition of prolyl oligopeptidase (POP): discovery of sulfonylfluoride peptidomimetics

Guardiola, S., Prades, R., Mendieta, L., Brouwer, A. J., Streefkerk, J., Nevola, L., Tarragó, T., Liskamp, R. M.J. and Giralt, E. (2018) Targeted covalent inhibition of prolyl oligopeptidase (POP): discovery of sulfonylfluoride peptidomimetics. Cell Chemical Biology, 25(8), 1037-1037.e4. (doi: 10.1016/j.chembiol.2018.04.013) (PMID:29779956)

Abstract

Prolyl oligopeptidase (POP), a serine protease highly expressed in the brain, has recently emerged as an enticing therapeutic target for the treatment of cognitive and neurodegenerative disorders. However, most reported inhibitors suffer from short duration of action, poor protease selectivity, and low blood-brain barrier (BBB) permeability, which altogether limit their potential as drugs. Here, we describe the structure-based design of the first irreversible, selective, and brain-permeable POP inhibitors. At low-nanomolar concentrations, these covalent peptidomimetics produce a fast, specific, and sustained inactivation of POP, both in vitro and in human cells. More importantly, they are >1,000-fold selective against two family-related proteases (DPPIV and FAP) and display high BBB permeability, as shown in both lipid membranes and MDCK cells.

• Item Type: Articles
• Additional Information: This study was funded by MINECO-FEDER (BIO 2016-75327-R) and Generalitat de Catalunya (XRB and 2017SGR-998).
• Keywords: CNS disorders, blood-brain barrier, covalent inhibitors, enzyme inhibitors, peptidomimetics.
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Liskamp, Professor Robert
• Authors: Guardiola, S., Prades, R., Mendieta, L., Brouwer, A. J., Streefkerk, J., Nevola, L., Tarragó, T., Liskamp, R. M.J., and Giralt, E.
• College/School: College of Science and Engineering > School of Chemistry
• Journal Name: Cell Chemical Biology
• Publisher: Elsevier (Cell Press)
• ISSN: 2451-9456
• ISSN (Online): 2451-9448
• Published Online: 17 May 2018