ABSTRACT: Pyroptosis is a caspase-1-dependent pro-inflammatory form of programmed cell death implicated in the pathogenesis of autoinflammatory diseases as well as in disorders characterized by excessive cell death and inflammation. Activation of NLRP3 inflammasome is a key event in the pyroptotic cascade. In this study, we describe the synthesis and chemical tuning of α,β-unsaturated electrophilic warheads toward the development of antipyroptotic compounds. Their pharmacological evaluation and structure−activity relationships are also described. Compound 9 was selected as a model of this series, and it proved to be a reactive Michael acceptor, irreversibly trapping thiol nucleophiles, which prevented both ATP- and nigericin-triggered pyroptosis of human THP-1 cells in a time- and concentration-dependent manner. Moreover, 9 and other structurally related compounds, inhibited caspase-1 and NLRP3 ATPase activities. Our findings can contribute to the development of covalent, multitarget antipyroptotic compounds targeting molecular components of the NLRP3 inflammasome regulatory pathway.
Electrophilic Warhead-Based Design of Compounds Preventing NLRP3 Inflammasome-Dependent Pyroptosis
COCCO, MATTIA;GARELLA, Davide;DI STILO, Antonella;BORRETTO, EMILY;STEVANATO, Livio;GIORGIS, Marta;MARINI, Elisabetta;FANTOZZI, Roberto;MIGLIO, Gianluca;BERTINARIA, Massimo
2014-01-01
Abstract
ABSTRACT: Pyroptosis is a caspase-1-dependent pro-inflammatory form of programmed cell death implicated in the pathogenesis of autoinflammatory diseases as well as in disorders characterized by excessive cell death and inflammation. Activation of NLRP3 inflammasome is a key event in the pyroptotic cascade. In this study, we describe the synthesis and chemical tuning of α,β-unsaturated electrophilic warheads toward the development of antipyroptotic compounds. Their pharmacological evaluation and structure−activity relationships are also described. Compound 9 was selected as a model of this series, and it proved to be a reactive Michael acceptor, irreversibly trapping thiol nucleophiles, which prevented both ATP- and nigericin-triggered pyroptosis of human THP-1 cells in a time- and concentration-dependent manner. Moreover, 9 and other structurally related compounds, inhibited caspase-1 and NLRP3 ATPase activities. Our findings can contribute to the development of covalent, multitarget antipyroptotic compounds targeting molecular components of the NLRP3 inflammasome regulatory pathway.File | Dimensione | Formato | |
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