Covalent Targeting As a Common Mechanism for Inhibiting NLRP3 Inflammasome Assembly

• DOI: 10.1021/acschembio.3c00330
• Publication Date: 2024-01-10T18:24:21Z
• Authors: Caroline Stanton; Jie Sun; Kayla Nutsch; Jessica D. Rosarda; Thu Nguyen; Chloris Li-Ma; Evert Njomen; Bruno Melillo; Sergei Kutseikin; Enrique Saez; Benjamin F. Cravatt; John R. Teijaro; R. Luke Wiseman; Michael J. Bollong
• Keywords: AIM2

The NLRP3 inflammasome is a cytosolic protein complex important for the regulation and secretion of inflammatory cytokines, including IL-1β IL-18. Aberrant overactivation implicated in numerous disorders. However, activation signaling remain poorly understood, limiting our ability to develop pharmacologic approaches target this complex. Here, we developed implemented high-throughput screen identify compounds that inhibit assembly activity. From screen, profile inhibition 20 new covalent across nine different chemical scaffolds, as well many known inhibitors. Intriguingly, results indicate possesses reactive cysteines on multiple domains whose targeting blocks Specifically, focusing compound VLX1570, which electrophilic moieties, demonstrate allows covalent, intermolecular cross-linking assembly. Our results, along with recent identification molecules activation, further support continued development cysteine residues regulate its