Development of Inhibitors of the Inflammasome

Abstract

The NLRP3 inflammasome is a multi-molecular protein complex which is responsible for the regulation and production of the pro-inflammatory cytokines interleukin-1β (IL-1β) and IL-18. Aberrant activation of the NLRP3 inflammasome can contribute to chronic inflammation, exacerbating non-communicable diseases such as Alzheimer’s disease. There is still uncertainty about the pathways involved in NLRP3 inflammasome activation, though chloride efflux is suggested as an important step. Some small molecule inhibitors of the NLRP3 inflammasome are known, however non are clinically approved (Chapter 1 Review). This medicinal chemistry thesis (journal format) contributes to the mechanism of activation of the inflammasome and its inhibition. NBC-19 is the leading NLRP3 inflammasome inhibitor in the Novel Boron Compound (NBC) series, designed at the University of Manchester. The SAR of the NBC’s was further explored, revealing the essential nature of the lipophilic CCl3 group and the oxazaborine ring (Chapter 2). Clinically available NSAIDs (fenamates) inhibit the NLRP3 inflammasome as a result of chloride channel inhibition, however the use of NSAIDs as NLRP3 therapeutics is precluded by their inhibition of COX enzymes. Following iterative rounds of guided medicinal chemistry, a lead series of chloride inhibiting compounds have emerged. These urea-based compounds exhibited improved NLRP3 inflammasome inhibition compared to the fenamates, together with no COX inhibition (Chapter 4). During these rounds of medicinal chemistry, symmetrical diarylsquaramide side-products were serendipitously found to activate the NLRP3 inflammasome. Diarylsquaramides are known transmembrane chloride transporters, and given the link between chloride efflux and NLRP3 inflammasome activation, these compounds may prove to be useful tools (Chapter 5). Future work aims to develop more potent inhibitors and activators of the NLRP3 inflammasome. Research continues to identify the specific chloride channels involved in the activation of the NLRP3 inflammasome in response to specific stimuli, which raises the possibility of developing selective chloride channel inhibitors depending on the NLRP3-dependent disease which is being targeted.

Date of Award	1 Aug 2022
Original language	English
Awarding Institution	The University of Manchester
Supervisor	Sally Freeman (Supervisor), Catherine Lawrence (Supervisor) & David Brough (Supervisor)