title: Electrophilic warhead-based design of compounds preventing NLRP3 inflammasome-dependent pyroptosis.
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.
authors.affiliation: Dipartimento di Scienza e Tecnologia del Farmaco, Università degli Studi di Torino , Via P. Giuria 9, 10125 Torino, Italy.
authors.forename: Mattia
authors.initials: M
authors.lastname: Cocco
authors.forename: Davide
authors.initials: D
authors.lastname: Garella
authors.forename: Antonella
authors.initials: A
authors.lastname: Di Stilo
authors.forename: Emily
authors.initials: E
authors.lastname: Borretto
authors.forename: Livio
authors.initials: L
authors.lastname: Stevanato
authors.forename: Marta
authors.initials: M
authors.lastname: Giorgis
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Marini
authors.forename: Roberto
authors.initials: R
authors.lastname: Fantozzi
authors.forename: Gianluca
authors.initials: G
authors.lastname: Miglio
authors.forename: Massimo
authors.initials: M
authors.lastname: Bertinaria
mesh_terms: D000251:Adenosine Triphosphatases / Q000037:antagonists & inhibitors; D000893:Anti-Inflammatory Agents / Q000737:chemistry* / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D002352:Carrier Proteins / Q000037:antagonists & inhibitors*; D020170:Caspase 1 / Q000737:chemistry; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D006801:Humans; D058847:Inflammasomes / Q000187:drug effects*; D007684:Kidney Tubules; D008264:Macrophages / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D008689:Methacrylates / Q000737:chemistry* / Q000494:pharmacology; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein
chemical_list: D000893:Anti-Inflammatory Agents; D002352:Carrier Proteins; D004791:Enzyme Inhibitors; D058847:Inflammasomes; D008689:Methacrylates; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C453881:NLRP3 protein, human; C000595869:ethyl 2-((2-chlorophenyl)(hydroxy)methyl)acrylate; D020170:Caspase 1; D000251:Adenosine Triphosphatases