Targeting the NLRP3 inflammasome for inflammatory disease therapy

The NOD-like receptor pyrin domain-containing 3 (NLRP3) inflammasome is a megadalton complex implicated in numerous inflammation-driven diseases including COVID-19, Alzheimer's disease, and gout. Although past efforts have focused on inhibiting IL-1β downstream of NLRP3 activation using drugs such as canakinumab, no FDA-approved NLRP3-targeted inhibitors are currently available. MCC950, a direct NLRP3 inhibitor, showed promise but exhibited off-target effects. Recent research has focused on optimizing the sulfonylurea-based MCC950 scaffold by leveraging recent structural and medicinal chemistry insights into the NLRP3 nucleotide-binding and oligomerization (NACHT) domain to improve solubility and clinical efficacy. In addition, oxidized DNA (oxDNA) has emerged as a key inflammasome trigger, and molecules targeting the pyrin domain have shown promise in inhibiting NLRP3 activation. This review discusses the role of NLRP3 in inflammation-related diseases, the status of ongoing clinical trials, and emerging small-molecule therapeutics targeting NLRP3.