Permeant fluorescent probes visualize the activation of SARM1 and uncover an anti-neurodegenerative drug candidate
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. Wi...
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2021-05-01
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| Series: | eLife |
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| Online Access: | https://elifesciences.org/articles/67381 |
| _version_ | 1818028399484993536 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Wan Hua Li |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-10T05:03:11Z |
| format | Article |
| id | doaj.art-ad4f471898f24bb6b9401388eb12196c |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-12-10T05:03:11Z |
| publishDate | 2021-05-01 |
| publisher | eLife Sciences Publications Ltd |
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| series | eLife |
| spelling | doaj.art-ad4f471898f24bb6b9401388eb12196c2022-12-22T02:01:19ZengeLife Sciences Publications LtdeLife2050-084X2021-05-011010.7554/eLife.67381Permeant fluorescent probes visualize the activation of SARM1 and uncover an anti-neurodegenerative drug candidateWan Hua Li0https://orcid.org/0000-0002-3881-5796Ke Huang1Yang Cai2Qian Wen Wang3Wen Jie Zhu4Yun Nan Hou5Sujing Wang6Sheng Cao7Zhi Ying Zhao8Xu Jie Xie9Yang Du10Chi-Sing Lee11https://orcid.org/0000-0002-3564-8224Hon Cheung Lee12https://orcid.org/0000-0002-6993-0121Hongmin Zhang13https://orcid.org/0000-0003-4356-3615Yong Juan Zhao14https://orcid.org/0000-0003-4564-1912State Key Laboratory of Chemical Oncogenomics, Key Laboratory of Chemical Genomics, Peking University Shenzhen Graduate School, Shenzhen, China; Ciechanover Institute of Precision and Regenerative Medicine, School of Life and Health Sciences, The Chinese University of Hong Kong, Shenzhen, ChinaDepartment of Chemistry, Hong Kong Baptist University, Kowloon Tong, Hong Kong, ChinaDepartment of Biology, Southern University of Science and Technology, Shenzhen, ChinaState Key Laboratory of Chemical Oncogenomics, Key Laboratory of Chemical Genomics, Peking University Shenzhen Graduate School, Shenzhen, ChinaState Key Laboratory of Chemical Oncogenomics, Key Laboratory of Chemical Genomics, Peking University Shenzhen Graduate School, Shenzhen, ChinaState Key Laboratory of Chemical Oncogenomics, Key Laboratory of Chemical Genomics, Peking University Shenzhen Graduate School, Shenzhen, ChinaState Key Laboratory of Chemical Oncogenomics, Key Laboratory of Chemical Genomics, Peking University Shenzhen Graduate School, Shenzhen, ChinaKobilka Institute of Innovative Drug Discovery, School of Life and Health Sciences, The Chinese University of Hong Kong, Shenzhen, ChinaState Key Laboratory of Chemical Oncogenomics, Key Laboratory of Chemical Genomics, Peking University Shenzhen Graduate School, Shenzhen, ChinaState Key Laboratory of Chemical Oncogenomics, Key Laboratory of Chemical Genomics, Peking University Shenzhen Graduate School, Shenzhen, ChinaKobilka Institute of Innovative Drug Discovery, School of Life and Health Sciences, The Chinese University of Hong Kong, Shenzhen, ChinaDepartment of Chemistry, Hong Kong Baptist University, Kowloon Tong, Hong Kong, ChinaState Key Laboratory of Chemical Oncogenomics, Key Laboratory of Chemical Genomics, Peking University Shenzhen Graduate School, Shenzhen, ChinaDepartment of Biology, Southern University of Science and Technology, Shenzhen, ChinaState Key Laboratory of Chemical Oncogenomics, Key Laboratory of Chemical Genomics, Peking University Shenzhen Graduate School, Shenzhen, China; Ciechanover Institute of Precision and Regenerative Medicine, School of Life and Health Sciences, The Chinese University of Hong Kong, Shenzhen, China; Shenzhen-Hong Kong Institute of Brain Science-Shenzhen Fundamental Research Institutions, Shenzhen, ChinaSARM1 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.https://elifesciences.org/articles/67381SARM1fluorescent probesbase-exchangeallosteric inhibitorsCryoEM structurecovalent inhibitors |
| spellingShingle | 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 Permeant fluorescent probes visualize the activation of SARM1 and uncover an anti-neurodegenerative drug candidate eLife SARM1 fluorescent probes base-exchange allosteric inhibitors CryoEM structure covalent inhibitors |
| title | Permeant fluorescent probes visualize the activation of SARM1 and uncover an anti-neurodegenerative drug candidate |
| title_full | Permeant fluorescent probes visualize the activation of SARM1 and uncover an anti-neurodegenerative drug candidate |
| title_fullStr | Permeant fluorescent probes visualize the activation of SARM1 and uncover an anti-neurodegenerative drug candidate |
| title_full_unstemmed | Permeant fluorescent probes visualize the activation of SARM1 and uncover an anti-neurodegenerative drug candidate |
| title_short | Permeant fluorescent probes visualize the activation of SARM1 and uncover an anti-neurodegenerative drug candidate |
| title_sort | permeant fluorescent probes visualize the activation of sarm1 and uncover an anti neurodegenerative drug candidate |
| topic | SARM1 fluorescent probes base-exchange allosteric inhibitors CryoEM structure covalent inhibitors |
| url | https://elifesciences.org/articles/67381 |
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