Inflammasomes play a vital role in our innate immune system by recognizing molecular danger signals associated with pathogenic invasion and endogenous host molecules correlated with cellular damage and stress. The NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome, is the most well elucidated inflammasome. Activation of the NLRP3 inflammasome stimulates the secretion of both interleukin IL-1β and IL-18. These two proinflammatory cytokines drive inflammation and promote a type of cell-death known as pyroptosis. Because studies suggest that the dysregulation of the NLRP3 inflammasome and IL-1β plays an important role in the pathogenesis of a variety of diseases, including Alzheimer’s disease and multiple sclerosis, developing novel NLRP3 inflammasome inhibitors capable of combatting these illnesses is of significant importance. However, NLRP3 inhibitors are currently lacking. Although glyburide, an anti-diabetic drug which stimulates the release of insulin from pancreatic b-cells, has been shown to inhibit the NLRP3 inflammasome in myeloid cells in vitro, it is not a realistic NLRP3 inhibitor in vivo because this drug would induce lethal hypoglycemia at concentrations required for NLRP3 inhibition. We hypothesized that it would be possible to alter the structure of glyburide to retain its NLRP3 inhibitory effect while eliminating this molecule’s insulin releasing activity. Currently, we have synthesized novel molecules, based off the structure of glyburide, that inhibit the production of IL-1β without affecting glucose levels. The initial results of our small molecule glyburide analogues are quite promising. So far, we have developed compounds that inhibit the production of IL-1β in J774.A1 macrophage cells, with IC50 values in the low nanomolar range.

Novel inhibitors of the NLRP3 inflammasome

254th National Meeting (2017)

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.