Guardiola_2018_Cell.Chem.Biol_25_1031

Reference

Title : Targeted Covalent Inhibition of Prolyl Oligopeptidase (POP): Discovery of Sulfonylfluoride Peptidomimetics - Guardiola_2018_Cell.Chem.Biol_25_1031
Author(s) : Guardiola S , Prades R , Mendieta L , Brouwer AJ , Streefkerk J , Nevola L , Tarrago T , Liskamp RMJ , Giralt E
Ref : Cell Chemical Biology , 25 :1031 , 2018
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.

PubMedSearch : Guardiola_2018_Cell.Chem.Biol_25_1031
PubMedID: 29779956

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Citations formats

Guardiola S, Prades R, Mendieta L, Brouwer AJ, Streefkerk J, Nevola L, Tarrago T, Liskamp RMJ, Giralt E (2018)
Targeted Covalent Inhibition of Prolyl Oligopeptidase (POP): Discovery of Sulfonylfluoride Peptidomimetics
Cell Chemical Biology 25 :1031

Guardiola S, Prades R, Mendieta L, Brouwer AJ, Streefkerk J, Nevola L, Tarrago T, Liskamp RMJ, Giralt E (2018)
Cell Chemical Biology 25 :1031