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Terazosin activates Pgk1 and Hsp90 to promote stress resistance

Xinping Chen1, Chunyue Zhao1, Xiaolong Li2

  • 11] 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.

Nature Chemical Biology
|November 11, 2014
PubMed

Insights

Terazosin (TZ), an existing drug, protects against organ damage and improves survival in stroke and sepsis models. It targets phosphoglycerate kinase 1 (Pgk1), enhancing Hsp90 activity for multistress resistance.

Area of Science:

  • Biochemistry
  • Pharmacology
  • Molecular Biology

Background:

  • Organ damage from conditions like sepsis and stroke requires new protective drugs.
  • Terazosin (TZ), an alpha-1 adrenergic receptor antagonist, is widely marketed.

Purpose of the Study:

  • To investigate the protective effects of terazosin (TZ) against organ damage.
  • To identify the molecular target and mechanism of action for TZ's protective effects.

Main Methods:

  • Enzymology and X-ray crystallography were used to determine TZ's target.
  • Rodent models of stroke and sepsis were employed to assess TZ's efficacy.
  • Studies examined the interaction between TZ, phosphoglycerate kinase 1 (Pgk1), and Hsp90.

Main Results:

  • Terazosin (TZ) demonstrated organ protection and improved survival in rodent models of stroke and sepsis.
  • TZ was found to bind and activate phosphoglycerate kinase 1 (Pgk1).
  • Activated Pgk1 likely enhances Hsp90 chaperone activity, promoting multistress resistance.

Conclusions:

  • Terazosin (TZ) exhibits a novel mechanism of action by targeting Pgk1.
  • This pathway suggests TZ's potential for treating stroke, sepsis, and other conditions involving organ damage.
  • TZ represents a promising candidate for rapid clinical translation due to its established safety profile.

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