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

Li，Wan Hua1,2; Huang，Ke3; Cai，Yang4; Wang，Qian Wen1; Zhu，Wen Jie1; Hou，Yun Nan1; Wang，Sujing1; Cao，Sheng5; Zhao，Zhi Ying1; Xie，Xu Jie1; Du，Yang5; Lee，Chi Sing3; Lee，Hon Cheung1; Zhang，Hongmin4; Zhao，Yong Juan1,2,6

2021-05-04

10.7554/eLife.67381

eLife   影响因子和分区

2050-084X

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.

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

SCI

英语

通讯

WOS:000656073200001

2-s2.0-85107085515

Scopus

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,Chinese University of Hong Kong,Shenzhen,China
3.Department of Chemistry,Hong Kong Baptist University,Hong Kong,Kowloon Tong,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,Chinese University of Hong Kong,Shenzhen,China
6.Shenzhen-Hong Kong Institute of Brain Science-Shenzhen Fundamental Research Institutions,Shenzhen,China

Li，Wan Hua,Huang，Ke,Cai，Yang,et al. Permeant fluorescent probes visualize the activation of SARM1 and uncover an anti-neurodegenerative drug candidate[J]. eLife,2021,10.

Li，Wan Hua.,Huang，Ke.,Cai，Yang.,Wang，Qian Wen.,Zhu，Wen Jie.,...&Zhao，Yong Juan.(2021).Permeant fluorescent probes visualize the activation of SARM1 and uncover an anti-neurodegenerative drug candidate.eLife,10.

Li，Wan Hua,et al."Permeant fluorescent probes visualize the activation of SARM1 and uncover an anti-neurodegenerative drug candidate".eLife 10(2021).