Functional Characterization of an Arylsulfonamide-Based Small-Molecule Inhibitor of the NLRP3 Inflammasome

Considerable evidence indicates that the NOD-like Receptor family pyrin domain-containing 3 (NLRP3) inflammasome plays key roles in human pathophysiology, suggesting it as a potential drug target. Currently, studies have yet to develop compounds that are promising therapeutics in the clinic by targeting the NLRP3 inflammasome. Herein, we aim to further biologically characterize a previously identified small-molecule inhibitor of the NLRP3 inflammasome from our group, YM-I-26, to confirm its functional activities. We showed that YM-I-26 is highly selective toward the NLRP3 inflammasome and binds to NLRP3 directly. A systemic analysis revealed YM-I-26 with inflammation-related and immunomodulatory activities by the Eurofins BioMAP Diversity PLUS panel. In addition, studies using the mouse microglia BV2 cell model demonstrated that YM-I-26 is not cytotoxic, improved the phagocytotic functions of BV2 cells toward beta-amyloid, and suppressed the production of cytokines of IL-1β and IL-10 upon the activation of the NLRP3 inflammasome. Collectively, our studies support the functional activities of YM-I-26 as a NLRP3 Inhibitor in physiologically relevant cell models, and warrant future studies of YM-I-26 and its analogs to advance the drug development as potential therapeutics.

NOD-like receptor family pyrin domain containing 3 (NLRP3); binding interaction; inhibitor; microglia; neuroinflammation; phagocytosis.