2. Academic Validation
  3. Permeant fluorescent probes visualize the activation of SARM1 and uncover an anti-neurodegenerative drug candidate

Permeant fluorescent probes visualize the activation of SARM1 and uncover an anti-neurodegenerative drug candidate

  • Elife. 2021 May 4;10:e67381. doi: 10.7554/eLife.67381.
Wan Hua Li 1 2,  Ke Huang 3,  Yang Cai 4,  Qian Wen Wang 1,  Wen Jie Zhu 1,  Yun Nan Hou 1,  Sujing Wang 1,  Sheng Cao 5,  Zhi Ying Zhao 1,  Xu Jie Xie 1,  Yang Du 5,  Chi-Sing Lee 3,  Hon Cheung Lee 1,  Hongmin Zhang 4,  Yong Juan Zhao 1 2 6
Affiliations

Affiliations

  • 1 State Key Laboratory of Chemical Oncogenomics, Key Laboratory of Chemical Genomics, Peking University Shenzhen Graduate School, Shenzhen, China.
  • 2 Ciechanover Institute of Precision and Regenerative Medicine, School of Life and Health Sciences, The Chinese University of Hong Kong, Shenzhen, China.
  • 3 Department of Chemistry, Hong Kong Baptist University, Kowloon Tong, Hong Kong, China.
  • 4 Department of Biology, Southern University of Science and Technology, Shenzhen, China.
  • 5 Kobilka Institute of Innovative Drug Discovery, School of Life and Health Sciences, The Chinese University of Hong Kong, Shenzhen, China.
  • 6 Shenzhen-Hong Kong Institute of Brain Science-Shenzhen Fundamental Research Institutions, Shenzhen, China.
PMID: 33944777 DOI: 10.7554/eLife.67381
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.

Keywords

ADP-ribosyl cyclase; CD38; CryoEM structure; NAADP; NAD; SARM1; allosteric inhibitors; base-exchange; biochemistry; cADPR; cell biology; chemical biology; covalent inhibitors; cyclic ADP-ribose; dHNN; fluorescent probes; human; mouse; nisoldipine.

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