Levering Mechanically Activated Piezo Channels for Potential Pharmacological Intervention

Author:

Xiao Bailong1

Affiliation:

1. State Key Laboratory of Membrane Biology; Tsinghua-Peking Joint Center for Life Sciences; IDG/McGovern Institute for Brain Research; Beijing Advanced Innovation Center for Structural Biology; and School of Pharmaceutical Sciences, Tsinghua University, Beijing 100084, China;

Abstract

The mechanically activated Piezo channels, including Piezo1 and Piezo2 in mammals, function as key mechanotransducers for converting mechanical force into electrochemical signals. This review highlights key evidence for the potential of Piezo channel drug discovery. First, both mouse and human genetic studies have unequivocally demonstrated the prominent role of Piezo channels in various mammalian physiologies and pathophysiologies, validating their potential as novel therapeutic targets. Second, the cryo-electron microscopy structure of the 2,547-residue mouse Piezo1 trimer has been determined, providing a solid foundation for studying its structure-function relationship and drug action mechanisms and conducting virtual drug screening. Third, Piezo1 chemical activators, named Yoda1 and Jedi1/2, have been identified through high-throughput screening assays, demonstrating the drugability of Piezo channels. However, the pharmacology of Piezo channels is in its infancy. By establishing an integrated drug discovery platform, we may hopefully discover and develop a fleet of Jedi masters for battling Piezo-related human diseases.

Publisher

Annual Reviews

Subject

Pharmacology,Toxicology

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