Permeant fluorescent probes visualize the activation of sarm1 and uncover an antineurodegenerative drug candidate

Wan Hua Li, Ke Huang, Yang Cai, Qian Wen Wang, Wen Jie Zhu, Yun Nan Hou, Sujing Wang, Sheng Cao, Zhi Ying Zhao, Xu Jie Xie, Yang Du, Chi Sing Lee*, Hon Cheung Lee, Hongmin Zhang, Yong Juan Zhao

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

11 Citations (Scopus)

Abstract

SARM1 regulates axonal degeneration through its NAD-metabolizing activity and is a drug target for neurodegenerative disorders. We designed and synthesized fluorescent conjugates of styryl derivative with pyridine to serve as substrates of SARM1, which exhibited large red shifts after conversion. With the conjugates, SARM1 activation was visualized in live cells following elevation of endogenous NMN or treatment with a cell-permeant NMN-analog. In neurons, imaging documented mouse SARM1 activation preceded vincristine-induced axonal degeneration by hours. Library screening identified a derivative of nisoldipine (NSDP) as a covalent inhibitor of SARM1 that reacted with the cysteines, especially Cys311 in its ARM domain and blocked its NMN-activation, protecting axons from degeneration. The Cryo-EM structure showed that SARM1 was locked into an inactive conformation by the inhibitor, uncovering a potential neuroprotective mechanism of dihydropyridines.

Original languageEnglish
Article numbere67381
JournaleLife
Volume10
DOIs
Publication statusPublished - 4 May 2021

Scopus Subject Areas

  • Neuroscience(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)

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