Please use this identifier to cite or link to this item:
http://hdl.handle.net/2445/122781
Title: | Targeted Covalent Inhibition of Prolyl Oligopeptidase (POP): Discovery of Sulfonylfluoride Peptidomimetics |
Author: | Guardiola Bagán, Salvador Prades, Roger Mendieta Martínez, Laura Brouwer, Arwin J. Streefkerk, Jelle Nevola, Laura Tarragó Clua, Maria Teresa Liskamp, Rob M. J. Giralt Lledó, Ernest |
Keywords: | Inhibidors enzimàtics Barrera hematoencefàlica Enzyme inhibitors Blood-brain barrier |
Issue Date: | 17-May-2018 |
Publisher: | Elsevier |
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. |
Note: | Versió postprint del document publicat a: http://dx.doi.org/10.1016/j.chembiol.2018.04.013 |
It is part of: | Cell Chemical Biology, 2018 |
URI: | http://hdl.handle.net/2445/122781 |
Related resource: | http://dx.doi.org/10.1016/j.chembiol.2018.04.013 |
ISSN: | 2451-9456 |
Appears in Collections: | Articles publicats en revistes (Institut de Recerca Biomèdica (IRB Barcelona)) |
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CellChemicalBiology_2018_Giralt.pdf | 532.92 kB | Adobe PDF | View/Open |
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