Novel GSDMD inhibitor GI-Y1 protects heart against pyroptosis and ischemia/reperfusion injury by blocking pyroptotic pore formation.

Activation of gasdermin D (GSDMD) and its concomitant cardiomyocyte pyroptosis are critically involved in multiple cardiac pathological conditions. Pharmacological inhibition or gene knockout of GSDMD could protect cardiomyocyte from pyroptosis and dysfunction. Thus, seeking and developing highly potent GSDMD inhibitors probably provide an attractive strategy for treating diseases targeting GSDMD. Through structure-based virtual screening, pharmacological screening and subsequent pharmacological validations, we preliminarily identified GSDMD inhibitor Y1 (GI-Y1) as a selective GSDMD inhibitor with cardioprotective effects. Mechanistically, GI-Y1 binds to GSDMD and inhibits lipid- binding and pyroptotic pore formation of GSDMD-N by targeting the Arg7 residue. Importantly, we confirmed the cardioprotective effect of GI-Y1 on myocardial I/R injury and cardiac remodeling by targeting GSDMD. More extensively, GI-Y1 also inhibited the mitochondrial binding of GSDMD-N and its concomitant mitochondrial dysfunction. The findings of this study identified a new drug (GI-Y1) for the treatment of cardiac disorders by targeting GSDMD, and provide a new tool compound for pyroptosis research. © 2023. Springer-Verlag GmbH Germany, part of Springer Nature.

Citation

Lingfeng Zhong, Jibo Han, Xiaoxi Fan, Zhouqing Huang, Lan Su, Xueli Cai, Shuang Lin, Xudong Chen, Weijian Huang, Shanshan Dai, Bozhi Ye. Novel GSDMD inhibitor GI-Y1 protects heart against pyroptosis and ischemia/reperfusion injury by blocking pyroptotic pore formation. Basic research in cardiology. 2023 Oct 02;118(1):40

Mesh Tags

Substances

PMID: 37782407

search → result