2. Academic Validation
  3. Terazosin activates Pgk1 and Hsp90 to promote stress resistance

Terazosin activates Pgk1 and Hsp90 to promote stress resistance

  • Nat Chem Biol. 2015 Jan;11(1):19-25. doi: 10.1038/nchembio.1657.
Xinping Chen 1,  Chunyue Zhao 1,  Xiaolong Li 2,  Tao Wang 1,  Yizhou Li 3,  Cheng Cao 3,  Yuehe Ding 4,  Mengqiu Dong 4,  Lorenzo Finci 5,  Jia-Huai Wang 6,  Xiaoyu Li 7,  Lei Liu 8
Affiliations

Affiliations

  • 1 1] State Key Laboratory of Biomembrane and Membrane Biotechnology, School of Life Sciences, Peking University, Beijing, China. [2] Beijing Institute for Brain Disorder and Beijing Tiantan Hospital, Capital Medical University, Beijing, China.
  • 2 1] School of Life Sciences, University of Science and Technology of China, Hefei, China. [2] School of Life Science, Peking University, Beijing, China.
  • 3 Key Laboratory of Bioorganic Chemistry and Molecular Engineering, College of Chemistry and Molecular Engineering, Peking University, Beijing, China.
  • 4 National Institute of Biological Sciences, Beijing, China.
  • 5 School of Life Science, Peking University, Beijing, China.
  • 6 1] School of Life Sciences, University of Science and Technology of China, Hefei, China. [2] School of Life Science, Peking University, Beijing, China. [3] Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA.
  • 7 1] Key Laboratory of Bioorganic Chemistry and Molecular Engineering, College of Chemistry and Molecular Engineering, Peking University, Beijing, China. [2] Key Laboratory of Chemical Genomics, School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School, Shenzhen, China.
  • 8 Beijing Institute for Brain Disorder and Beijing Tiantan Hospital, Capital Medical University, Beijing, China.
PMID: 25383758 DOI: 10.1038/nchembio.1657
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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