Novel anti-thrombotic agent for modulation of protein disulfide isomerase family member ERp57 for prophylactic therapy.

Abstract

Protein disulfide isomerase (PDI) family members including PDI and ERp57 emerge as novel targets for anti-thrombotic treatments, but chemical agents with selectivity remain to be explored. We previously reported a novel derivative of danshensu (DSS), known as ADTM, displayed strong cardioprotective effects against oxidative stress-induced cellular injury in vitro and acute myocardial infarct in vivo. Herein, using chemical proteomics approach, we identified ERp57 as a major target of ADTM. ADTM displayed potent inhibitory effects on the redox activity of ERp57, inhibited the adenosine diphosphate (ADP)-induced expressions of P-selectin and αIIbβ3 integrin, and disrupted the interaction between ERp57 and αIIbβ3. In addition, ADTM inhibited both arachidonic acid (AA)-induced and ADP-induced platelet aggregation in vitro. Furthermore, ADTM significantly inhibited rat platelet aggregation and thrombus formation in vivo. Taken together, ADTM represents a promising candidate for anti-thrombotic therapy targeting ERp57.

• Authors: Guozhen Cui, Luchen Shan, Lin Guo, Ivan Keung Chu, Guohui Li, Quan Quan, Yun Zhao, Cheong Meng Chong, Zaijun Zhang, Pei Yu, Maggie Pui Man Hoi, Yewei Sun, Yuqiang Wang, Simon MingYuen Lee
• Journal: Scientific reports (Sci Rep) Vol. 5 Pg. 10353 (Jun 03 2015) ISSN: 2045-2322 [Electronic] England
• PMID: 26037049 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Cell Adhesion Molecules
• Chlorides
• Ferric Compounds
• Fibrinolytic Agents
• Lactates
• Microfilament Proteins
• P-Selectin
• Phosphoproteins
• Platelet Glycoprotein GPIIb-IIIa Complex
• vasodilator-stimulated phosphoprotein
• 3,4-dihydroxyphenyllactic acid
• Adenosine Diphosphate
• Heme Oxygenase-1
• Protein Disulfide-Isomerases
• PDIA3 protein, human
• ferric chloride

Topics

• Adenosine Diphosphate (metabolism)
• Animals
• Blood Platelets (drug effects, metabolism)
• Cell Adhesion Molecules (metabolism)
• Chlorides (adverse effects)
• Disease Models, Animal
• Enzyme Activation
• Ferric Compounds (adverse effects)
• Fibrinolytic Agents (chemistry, pharmacology)
• Gene Expression Regulation (drug effects)
• Heme Oxygenase-1 (metabolism)
• Humans
• Lactates (chemistry, pharmacology)
• Microfilament Proteins (metabolism)
• Models, Biological
• P-Selectin (genetics, metabolism)
• Phosphoproteins (metabolism)
• Phosphorylation
• Platelet Activation
• Platelet Aggregation (drug effects)
• Platelet Glycoprotein GPIIb-IIIa Complex (metabolism)
• Protein Binding
• Protein Disulfide-Isomerases (metabolism)
• Proteomics
• Rats
• Thrombosis (drug therapy, etiology)
• Venous Thrombosis (etiology)