Discovery of a novel 1,3,4-oxadiazol-2-one-based NLRP3 inhibitor as a pharmacological agent to mitigate cardiac and metabolic complications in an experimental model of diet-induced metaflammation

TL;DR

This study reports the discovery and testing of a novel 1,3,4-oxadiazol-2-one-based NLRP3 inhibitor, INF200, which effectively reduces inflammation and cardiac damage in models of diet-induced metaflammation, showing therapeutic potential.

Contribution

The paper introduces a new NLRP3 inhibitor, INF200, with demonstrated efficacy in reducing inflammation and cardiac injury in experimental models, advancing potential treatments for obesity-related complications.

Findings

INF200 prevents NLRP3-dependent pyroptosis in human macrophages.

INF200 improves metabolic profiles and reduces cardiac biomarkers in HFD-fed rats.

INF200 limits myocardial damage and reduces oxidative stress post-ischemia.

Abstract

Inspired by the recent advancements in understanding the binding mode of sulfonylurea-based NLRP3 inhibitors to the NLRP3 sensor protein, we developed new NLRP3 inhibitors by replacing the central sulfonylurea moiety with different heterocycles. Computational studies evidenced that some of the designed compounds were able to maintain important interaction within the NACHT domain of the target protein similarly to the most active sulfonylurea-based NLRP3 inhibitors. Among the studied compounds, the 1,3,4-oxadiazol-2-one derivative 5 (INF200) showed the most promising results being able to prevent NLRP3-dependent pyroptosis triggered by LPS/ATP and LPS/MSU by 66.3 +/- 6.6% and 61.6 +/- 11.5% and to reduce IL-1\b{eta} release (35.5 +/- 8.8 % {\mu}M) at 10 {\mu}M in human macrophages. The selected compound INF200 (20 mg/kg/day) was then tested in an in vivo rat model of high-fat diet (HFD)-induced metaflammation to evaluate its beneficial cardiometabolic effects. INF200 significantly counteracted HFD-dependent "anthropometric" changes, improved glucose and lipid profiles, and attenuated systemic inflammation and biomarkers of cardiac dysfunction (particularly BNP). Hemodynamic evaluation on Langendorff model indicate that INF200 limited myocardial damage-dependent ischemia/reperfusion injury (IRI) by improving post-ischemic systolic recovery and attenuating cardiac contracture, infarct size, and LDH release, thus reversing the exacerbation of obesity-associated damage. Mechanistically, in post-ischemic hearts, IFN200 reduced IRI-dependent NLRP3 activation, inflammation, and oxidative stress. These results highlight the potential of the novel NLRP3 inhibitor, INF200, and its ability to reverse the unfavorable cardio-metabolic dysfunction associated with obesity.