Pharmacological Inhibition of the NLRP3 Inflammasome: Structure, Molecular Activation, and Inhibitor-NLRP3 Interaction

nucleotide-binding, oligomeriza-tion domain-like receptor family pyrin domain con-taining 3 (NLRP3) inflammasome is a multiprotein complex that combines sensing, regulation, and effec-tor functions to regulate inflammation in health and disease. NLRP3 is activated by a diverse range of in-flammation-instigating signals known as pathogen associated molecular patterns and danger associated molecular patterns. Upon activation, NLRP3 oligo-merizes and recruits partner proteins to form a su-pramolecular platform to process the maturation and release of interleukin (IL)-1b, IL-18, and gasdermin D, major mediators of inflammation and inflammatory cell death termed pyroptosis. The NLRP3 inflamma-some has been implicated in the pathogenesis of a wide range of disease conditions, including chronic inflammatory disease that are associated with lifestyle and dietary changes, aging, and environmental expo-sures, and have become the leading cause of death worldwide. Pharmacological targeting of NLRP3 and signaling demonstrated promising efficacy in ameliorat-ing a list of disease conditions in animal models. These findings underscore the potential and importance ofNLRP3 as a druggable target for treating a range of diseases. In this review, recent progress in under-standing the structure and mechanism of action of the NLRP3 inflammasome is discussed with focus on pharmacological inhibition of NLRP3 by small mole-cule inhibitors. New structural and mechanistic in-sights into NLRP3 activation and inhibitor-NLRP3 interactions would aid in the rational design and pharmacological evaluation of NLRP3 inhibitors for treatment of human disease.