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 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 GSDMD cleavage nor the upstream inflammasome activation in mouse immortalized bone marrow-derived macrophages. pore-forming and mature IL-1b release. Collectively, our findings provide a new molecule with the potential for translational application in GSDMD-associated inflammatory diseases. The Journal of Immunology, 2022, 209: 820-828.

Automated summary

Pyroptosis is a key inflammatory form of cell death that plays an important role in the progression of many inflammatory diseases. In this study, we conducted a screening of compounds based on in silico docking and found that C202-2729 could significantly attenuate the severity of experimental autoimmune encephalomyelitis (EAE) and showed comparable effects to the clinical drug teriflunomide. Furthermore, we found that C202-2729 did not affect GSDMD cleavage, upstream inflammasome activation, pore formation, and mature IL-1b release in mouse macrophages. These findings suggest that C202-2729 may have potential for translational application in GSDMD-associated inflammatory diseases.