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Terazosin activates Pgk1 and Hsp90 to promote stress resistance

Nature Chemical Biology volume 11, pages 19–25 (2015)Cite this article

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Abstract

Drugs that can protect against organ damage are urgently needed, especially for diseases such as sepsis and brain stroke. We discovered that terazosin (TZ), a widely marketed α1-adrenergic receptor antagonist, alleviated organ damage and improved survival in rodent models of stroke and sepsis. Through combined studies of enzymology and X-ray crystallography, we discovered that TZ binds a new target, phosphoglycerate kinase 1 (Pgk1), and activates its enzymatic activity, probably through 2,4-diamino-6,7-dimethoxyisoquinoline′s ability to promote ATP release from Pgk1. Mechanistically, the ATP generated from Pgk1 may enhance the chaperone activity of Hsp90, an ATPase known to associate with Pgk1. Upon activation, Hsp90 promotes multistress resistance. Our studies demonstrate that TZ has a new protein target, Pgk1, and reveal its corresponding biological effect. As a clinical drug, TZ may be quickly translated into treatments for diseases including stroke and sepsis.

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Figure 1: TZ blocks apoptosis in cultured mammalian cells.
Figure 2: Pgk1 as the target of TZ.
Figure 3: Crystal structure of Pgk1 and TZ binding.
Figure 4: The antiapoptosis effect of TZ was dependent on Hsp90.
Figure 5: TZ shows multiple stress resistance in flies and rodents.

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Acknowledgements

This work was supported by the Chinese Ministry of Science and Technology (2013CB530700), the National Natural Science Foundation of China (NSFC31171324) and the Beijing Institute for Brain Disorder and Beijing Tiantan Hospital, Capital Medical University, China to L.L. and by the Ministry of Education of China and US National Institutes of Health grant HL48675 and funds from the Peking-Tsinghua Center for Life Sciences to J.W. We also acknowledge the Ministry of Science and Technology Basic Research Program (2011CB809100), the National Natural Science Foundation of China (21272016) and the Doctoral Fund of Ministry of Education of China (20120001110083) to Xiaoyu Li. We thank. L. Lai (Peking University) for her generous support in the ITC experiments. We thank the staff members at the Shanghai Synchrotron Radiation Facility and KEK-PF for generous support.

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Author notes

  1. Xinping Chen, Chunyue Zhao, Xiaolong Li and Tao Wang: These authors contributed equally to this work.

Authors and Affiliations

  1. State Key Laboratory of Biomembrane and Membrane Biotechnology, School of Life Sciences, Peking University, Beijing, China

    Xinping Chen, Chunyue Zhao & Tao Wang

  2. Beijing Institute for Brain Disorder and Beijing Tiantan Hospital, Capital Medical University, Beijing, China

    Xinping Chen, Chunyue Zhao, Tao Wang & Lei Liu

  3. School of Life Sciences, University of Science and Technology of China, Hefei, China

    Xiaolong Li & Jia-huai Wang

  4. School of Life Science, Peking University, Beijing, China

    Xiaolong Li, Lorenzo Finci & Jia-huai Wang

  5. Key Laboratory of Bioorganic Chemistry and Molecular Engineering, College of Chemistry and Molecular Engineering, Peking University, Beijing, China

    Yizhou Li, Cheng Cao & Xiaoyu Li

  6. National Institute of Biological Sciences, Beijing, China

    Yuehe Ding & Mengqiu Dong

  7. Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA

    Jia-huai Wang

  8. Key Laboratory of Chemical Genomics, School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School, Shenzhen, China

    Xiaoyu Li

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Contributions

X.C., C.Z., T.W. and L.L. designed the experiments. X.C., C.Z. and T.W. performed the biological experiments. Xiaolong Li, L.F. and J.W. performed the crystal structure study. Y.D. and M.D. performed MS analysis. Y.L. and C.C. performed the chemical synthesis. Xiaoyu Li designed the chemical study. X.C., C.Z., J.W., Xiaoyu Li and L.L. wrote the manuscript.

Corresponding authors

Correspondence to Jia-huai Wang, Xiaoyu Li or Lei Liu.

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Competing interests

The authors declare competing financial interests for the novel use of TZ and its related chemicals to target Pgk1 and their related disease treatments. The authors have patented TZ for related disease treatments under patent numbers ZL 2011 1 0413931.0 and 201110412182.X at the Chinese Patent Office.

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Supplementary Results, Supplementary Table 1 and Supplementary Figures 1–17. (PDF 2061 kb)

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Procedures for chemical synthesis (DOC 210 kb)

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Chen, X., Zhao, C., Li, X. et al. Terazosin activates Pgk1 and Hsp90 to promote stress resistance. Nat Chem Biol 11, 19–25 (2015). https://doi.org/10.1038/nchembio.1657

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