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

doi:10.7554/eLife.67381

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

Department of Chemistry

Research output: Contribution to journal › Journal article › peer-review

41 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 language	English
Article number	e67381
Number of pages	21
Journal	eLife
Volume	10
DOIs	https://doi.org/10.7554/eLife.67381
Publication status	Published - 4 May 2021

Scopus Subject Areas

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

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.7554/eLife.67381

Cite this

@article{a167cb0a594c4e57b15e0fb6d1c7e792,

title = "Permeant fluorescent probes visualize the activation of sarm1 and uncover an antineurodegenerative drug candidate",

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.",

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

note = "Funding Information: Funder Grant reference number Author Ministry of Science and Technology of the People?s Republic of China National Science Foundation of China 2019YFA0906000 Hongmin Zhang 31871401 Yong Juan Zhao Hong Kong Baptist University RC-SGT2/18-19/SCI/005 Chi-Sing Lee Hong Kong Baptist University RC-ICRS-18-19-01A Chi-Sing Lee The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication. Funding Information: National Science Foundation of China Publisher Copyright: {\textcopyright} Li et al.",

year = "2021",

month = may,

day = "4",

doi = "10.7554/eLife.67381",

language = "English",

volume = "10",

journal = "eLife",

issn = "2050-084X",

publisher = "eLife Sciences Publications",

}

TY - JOUR

T1 - Permeant fluorescent probes visualize the activation of sarm1 and uncover an antineurodegenerative drug candidate

AU - Li, Wan Hua

AU - Huang, Ke

AU - Cai, Yang

AU - Wang, Qian Wen

AU - Zhu, Wen Jie

AU - Hou, Yun Nan

AU - Wang, Sujing

AU - Cao, Sheng

AU - Zhao, Zhi Ying

AU - Xie, Xu Jie

AU - Du, Yang

AU - Lee, Chi Sing

AU - Lee, Hon Cheung

AU - Zhang, Hongmin

AU - Zhao, Yong Juan

N1 - Funding Information: Funder Grant reference number Author Ministry of Science and Technology of the People?s Republic of China National Science Foundation of China 2019YFA0906000 Hongmin Zhang 31871401 Yong Juan Zhao Hong Kong Baptist University RC-SGT2/18-19/SCI/005 Chi-Sing Lee Hong Kong Baptist University RC-ICRS-18-19-01A Chi-Sing Lee The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication. Funding Information: National Science Foundation of China Publisher Copyright: © Li et al.

PY - 2021/5/4

Y1 - 2021/5/4

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85107085515&partnerID=8YFLogxK

U2 - 10.7554/eLife.67381

DO - 10.7554/eLife.67381

M3 - Journal article

C2 - 33944777

AN - SCOPUS:85107085515

SN - 2050-084X

VL - 10

JO - eLife

JF - eLife

M1 - e67381

ER -

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

Abstract

Scopus Subject Areas

UN SDGs

Access to Document

Other files and links

Fingerprint

Cite this