Pharmacological inhibition of NLRP3 inflammasome activation may offer a new option in the treatment of inflammatory bowel disease. In this work, we report the design, synthesis, and biological screening of a series of acrylate derivatives as NLRP3 inhibitors. The in vitro determination of reactivity, cytotoxicity, NLRP3 ATPase inhibition, and antipyroptotic properties allowed the selection of 11 (INF39), a nontoxic, irreversible NLRP3 inhibitor able to decrease interleukin-1β release from macrophages. Bioluminescence resonance energy transfer experiments proved that this compound was able to directly interfere with NLRP3 activation in cells. In vivo studies confirmed the ability of the selected lead to alleviate the effects of colitis induced by 2,4-dinitrobenzenesulfonic acid in rats after oral administration.

Development of an Acrylate Derivative Targeting the NLRP3 Inflammasome for the Treatment of Inflammatory Bowel Disease

COCCO, MATTIA;GIORGIS, Marta;MARINI, Elisabetta;COSTALE, Annalisa;MIGLIO, Gianluca;BERTINARIA, Massimo
Last
2017

Abstract

Pharmacological inhibition of NLRP3 inflammasome activation may offer a new option in the treatment of inflammatory bowel disease. In this work, we report the design, synthesis, and biological screening of a series of acrylate derivatives as NLRP3 inhibitors. The in vitro determination of reactivity, cytotoxicity, NLRP3 ATPase inhibition, and antipyroptotic properties allowed the selection of 11 (INF39), a nontoxic, irreversible NLRP3 inhibitor able to decrease interleukin-1β release from macrophages. Bioluminescence resonance energy transfer experiments proved that this compound was able to directly interfere with NLRP3 activation in cells. In vivo studies confirmed the ability of the selected lead to alleviate the effects of colitis induced by 2,4-dinitrobenzenesulfonic acid in rats after oral administration.
60
9
3656-3671
3671
http://pubs.acs.org
Cocco, Mattia; Pellegrini, Carolina; Martínez-Banaclocha, Helios; Giorgis, Marta; Marini, Elisabetta; Costale, Annalisa; Miglio, Gianluca; Fornai, Matteo; Antonioli, Luca; López-Castejón, Gloria; Tapia-Abellán, Ana; Angosto, Diego; Hafner-Bratkovič, Iva; Regazzoni, Luca; Blandizzi, Corrado; Pelegrín, Pablo; Bertinaria, Massimo
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/2318/1635532
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