title: 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.affiliation: 1] State Key Laboratory of Quality Research in Chinese Medicine and Institute of Chinese Medical Sciences, University of Macau, Macao, China [2] Department of Bioengineering, Zhuhai Campus of Zunyi Medical University, Guangdong, Zhuhai, China.
authors.forename: Guozhen
authors.initials: G
authors.lastname: Cui
authors.affiliation: 1] Institute of New Drug Research, Collage of Pharmacy, Jinan University, Guangzhou, China [2] Key Laboratory of Cardiovascular Medicine Research, Ministry of Education, Harbin Medical University, Harbin, China.
authors.forename: Luchen
authors.initials: L
authors.lastname: Shan
authors.affiliation: Institute of New Drug Research, Collage of Pharmacy, Jinan University, Guangzhou, China.
authors.forename: Lin
authors.initials: L
authors.lastname: Guo
authors.affiliation: Department of Chemistry, The University of Hong Kong, Hong Kong, China.
authors.forename: Ivan Keung
authors.initials: IK
authors.lastname: Chu
authors.affiliation: Department of Chemistry, The University of Hong Kong, Hong Kong, China.
authors.forename: Guohui
authors.initials: G
authors.lastname: Li
authors.affiliation: Institute of New Drug Research, Collage of Pharmacy, Jinan University, Guangzhou, China.
authors.forename: Quan
authors.initials: Q
authors.lastname: Quan
authors.affiliation: Department of Chemistry, The University of Hong Kong, Hong Kong, China.
authors.forename: Yun
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: State Key Laboratory of Quality Research in Chinese Medicine and Institute of Chinese Medical Sciences, University of Macau, Macao, China.
authors.forename: Cheong Meng
authors.initials: CM
authors.lastname: Chong
authors.affiliation: Institute of New Drug Research, Collage of Pharmacy, Jinan University, Guangzhou, China.
authors.forename: Zaijun
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Institute of New Drug Research, Collage of Pharmacy, Jinan University, Guangzhou, China.
authors.forename: Pei
authors.initials: P
authors.lastname: Yu
authors.affiliation: State Key Laboratory of Quality Research in Chinese Medicine and Institute of Chinese Medical Sciences, University of Macau, Macao, China.
authors.forename: Maggie Pui Man
authors.initials: MP
authors.lastname: Hoi
authors.affiliation: Institute of New Drug Research, Collage of Pharmacy, Jinan University, Guangzhou, China.
authors.forename: Yewei
authors.initials: Y
authors.lastname: Sun
authors.affiliation: Institute of New Drug Research, Collage of Pharmacy, Jinan University, Guangzhou, China.
authors.forename: Yuqiang
authors.initials: Y
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Quality Research in Chinese Medicine and Institute of Chinese Medical Sciences, University of Macau, Macao, China.
authors.forename: Simon MingYuen
authors.initials: SM
authors.lastname: Lee
mesh_terms: D000244:Adenosine Diphosphate / Q000378:metabolism; D000818:Animals; D001792:Blood Platelets / Q000187:drug effects / Q000378:metabolism; D015815:Cell Adhesion Molecules / Q000378:metabolism; D002712:Chlorides / Q000009:adverse effects; D004195:Disease Models, Animal; D004789:Enzyme Activation; D005290:Ferric Compounds / Q000009:adverse effects; D005343:Fibrinolytic Agents / Q000737:chemistry / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects; D051547:Heme Oxygenase-1 / Q000378:metabolism; D006801:Humans; D007773:Lactates / Q000737:chemistry / Q000494:pharmacology; D008840:Microfilament Proteins / Q000378:metabolism; D008954:Models, Biological; D019007:P-Selectin / Q000235:genetics / Q000378:metabolism; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation; D015539:Platelet Activation; D010974:Platelet Aggregation / Q000187:drug effects; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000378:metabolism; D011485:Protein Binding; D019704:Protein Disulfide-Isomerases / Q000378:metabolism*; D040901:Proteomics; D051381:Rats; D013927:Thrombosis / Q000188:drug therapy / Q000209:etiology; D020246:Venous Thrombosis / Q000209:etiology; D000098662:Vasodilator-Stimulated Phosphoprotein
chemical_list: D015815:Cell Adhesion Molecules; D002712:Chlorides; D005290:Ferric Compounds; D005343:Fibrinolytic Agents; D007773:Lactates; D008840:Microfilament Proteins; D019007:P-Selectin; D010750:Phosphoproteins; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D000098662:Vasodilator-Stimulated Phosphoprotein; C035055:3,4-dihydroxyphenyllactic acid; D000244:Adenosine Diphosphate; D051547:Heme Oxygenase-1; D019704:Protein Disulfide-Isomerases; C085868:PDIA3 protein, human; C024555:ferric chloride