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CellChemicalBiology_2018_Giralt.pdf (532.92 KB)

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2018-05-17

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Si us plau utilitzeu sempre aquest identificador per citar o enllaçar aquest document: https://hdl.handle.net/2445/122781

Targeted Covalent Inhibition of Prolyl Oligopeptidase (POP): Discovery of Sulfonylfluoride Peptidomimetics

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Recurs relacionat

http://dx.doi.org/10.1016/j.chembiol.2018.04.013

Resum

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.

Matèries

Inhibidors enzimàtics, Barrera hematoencefàlica

Matèries (anglès)

Enzyme inhibitors, Blood-brain barrier

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Articles publicats en revistes (Institut de Recerca Biomèdica (IRB Barcelona))

Citació

GUARDIOLA BAGÁN, Salvador, et al. Targeted Covalent Inhibition of Prolyl Oligopeptidase (POP): Discovery of Sulfonylfluoride Peptidomimetics. Cell Chemical Biology. 2018. ISSN 2451-9456. [consulted: 23 of May of 2026]. Available at: https://hdl.handle.net/2445/122781

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