Squaramides enhance NLRP3 inflammasome activation by lowering intracellular potassium.

The NLRP3 inflammasome is a component of the inflammatory response to infection and injury, orchestrating the maturation and release of the pro-inflammatory cytokines interleukin-1β (IL-1β), IL-18, and triggering pyroptotic cell death. Appropriate levels of NLRP3 activation are needed to avoid excessive tissue damage while ensuring host protection. Here we report a role for symmetrical diarylsquaramides as selective K efflux-dependent NLRP3 inflammasome enhancers.

Selective inhibition of the K efflux sensitive NLRP3 pathway by Cl channel modulation.

The NLRP3 inflammasome regulates production of the pro-inflammatory cytokines interleukin-1β (IL-1β) and IL-18, and contributes to inflammation exacerbating disease. Fenamate non-steroidal anti-inflammatory drugs (NSAIDs) were recently described as NLRP3 inflammasome inhibitors chloride channel inhibition. Fenamate NSAIDs inhibit cyclooxygenase (COX) enzymes, limiting their potential as therapeutics for NLRP3-associated diseases due to established side effects.

LRRC8A is essential for hypotonicity-, but not for DAMP-induced NLRP3 inflammasome activation.

The NLRP3 inflammasome is a multi-molecular protein complex that converts inactive cytokine precursors into active forms of IL-1β and IL-18. The NLRP3 inflammasome is frequently associated with the damaging inflammation of non-communicable disease states and is considered an attractive therapeutic target. However, there is much regarding the mechanism of NLRP3 activation that remains unknown.

Is Targeting the Inflammasome a Way Forward for Neuroscience Drug Discovery?

Neuroinflammation is becoming increasingly recognized as a critical factor in the pathology of both acute and chronic neurological conditions. Inflammasomes such as the one formed by NACHT, LRR, and PYD domains containing protein 3 (NLRP3) are key regulators of inflammation due to their ability to induce the processing and secretion of interleukin 1β (IL-1β). IL-1β has previously been identified as a potential therapeutic target in a variety of conditions due to its ability to promote neuronal damage under conditions of injury.

Design, Synthesis and Evaluation of Oxazaborine Inhibitors of the NLRP3 Inflammasome.

The NLRP3 inflammasome is an important regulator of the sterile inflammatory response, and its activation by host-derived sterile molecules leads to the intracellular activation of caspase-1, processing of the pro-inflammatory cytokines interleukin-1β (IL-1β)/IL-18, and pyroptotic cell death. Inappropriate activation of NLRP3 drives a chronic inflammatory response and is implicated in several non-communicable diseases, including gout, atherosclerosis, type II diabetes and Alzheimer's disease. In this study, we report the design, synthesis and biological evaluation of novel boron compounds (NBCs) as NLRP3 inflammasome inhibitors.