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Identification of a Small Molecule with Strong Anti-Inflammatory Activity in Experimental Autoimmune Encephalomyelitis and Sepsis through Blocking Gasdermin D Activation

Pyroptosis is a key inflammatory form of cell death participating in the progression of many inflammatory diseases, such as experimental autoimmune encephalomyelitis (EAE) and sepsis. Identification of small molecules to inhibit pyroptosis is emerging as an attractive strategy. In this study, we performed a screening based on in silico docking of compounds on the reported Gasdermin D (GSDMD) three-dimensional structure and found C202-2729 demonstrated strong anti-inflammatory effects in both endotoxin shock and EAE mouse models. Oral administration of C202-2729 was capable of attenuating EAE disease severity significantly and has the comparable effects to teriflunomide, the first-line clinical drug of multiple sclerosis. We found C202-2729 remarkably suppressed macrophage and T cell–associated immune inflammation. Mechanistically, C202-2729 neither impact GSDMD cleavage nor the upstream inflammasome activation in mouse immortalized bone marrow–derived macrophages. However, C202-2729 exposure significantly repressed the IL-1β secretion and cell pyroptosis. We found C202-2729 directly bonds to the N terminus of GSDMD and blocks the migration of the N-terminal GSDMD fragment to cell membrane, restraining the pore-forming and mature IL-1β release. Collectively, our findings provide a new molecule with the potential for translational application in GSDMD-associated inflammatory diseases. Key Points C202-2729 significantly attenuates endotoxin shock and EAE. C202-2729 selectively binds to the N terminus of GSDMD. C202-2729 blocks the migration of GSDMDNT to cell membrane.