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

Pharmacol Rev. 2023 May;75(3):487-520. doi: 10.1124/pharmrev.122.000629. Epub 2023 Jan 20.ABSTRACTThe nucleotide-binding, oligomerization domain-like receptor family pyrin domain containing 3 (NLRP3) inflammasome is a multiprotein complex that combines sensing, regulation, and effector functions to regulate inflammation in health and disease. NLRP3 is activated by a diverse range of inflammation-instigating signals known as pathogen associated molecular patterns and danger associated molecular patterns. Upon activation, NLRP3 oligomerizes and recruits partner proteins to form a supramolecular platform to process the maturation and release of interleukin (IL)-1β, IL-18, and gasdermin D, major mediators of inflammation and inflammatory cell death termed pyroptosis. The NLRP3 inflammasome 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 exposures, and have become the leading cause of death worldwide. Pharmacological targeting of NLRP3 and signaling demonstrated promising efficacy in ameliorating a list of disease conditions in animal models. These findings underscore the potential and importance of NLRP3 as a druggable target for treating a range of diseases. In this review, recent progress in understanding the structure and mechanism of action of the NLRP3 inflammasome is discussed with focus on pharmacological inhibition of NLRP...

Source: Pharmacognosy Reviews - January 20, 2023 Category: Drugs & Pharmacology Authors: Qiang Ma Source Type: research