Terazosin activates Pgk1 and Hsp90 to promote stress resistance.

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.

• Authors: Xinping Chen, Chunyue Zhao, Xiaolong Li, Tao Wang, Yizhou Li, Cheng Cao, Yuehe Ding, Mengqiu Dong, Lorenzo Finci, Jia-Huai Wang, Xiaoyu Li, Lei Liu
• Journal: Nature chemical biology (Nat Chem Biol) Vol. 11 Issue 1 Pg. 19-25 (Jan 2015) ISSN: 1552-4469 [Electronic] United States
• PMID: 25383758 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Adrenergic alpha-1 Receptor Antagonists
• Cytokines
• HSP90 Heat-Shock Proteins
• Terazosin
• Pgk1 protein, mouse
• Phosphoglycerate Kinase
• Prazosin

Topics

• Adrenergic alpha-1 Receptor Antagonists (pharmacology)
• Animals
• Apoptosis (drug effects)
• Cells, Cultured
• Cytokines (metabolism)
• HSP90 Heat-Shock Proteins (chemistry, drug effects)
• Infarction, Middle Cerebral Artery (drug therapy, pathology)
• Mice
• Models, Molecular
• Phosphoglycerate Kinase (chemistry, drug effects)
• Prazosin (analogs & derivatives, pharmacology)
• Protein Conformation
• Rats
• Sepsis (drug therapy)
• Stress, Physiological (drug effects)
• Stroke (drug therapy)