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Novel derivative of Danshensu acts as anti-thrombotic agent for modulation of protein disulfide isomerase family member ERp57

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中国药理学与毒理学杂志 2015年第S1期29卷 34-34页

作者： Guo-zhenCUI Lu-chenSHAN LinGUO IvanKeungCHU Guo-huiLI QuanQUAN YunZHAO Chenong-mengCHONG ZaijunZHANG PeiYU Pui-manHOI Ye-weiSUN Yu-qiangWANG Simonming-yuenLEE State Key Laboratory of Quality Research in Chinese Medicine and Institute of Chinese Medical Sciences University of Macao Macao China Institute of New Drug Research Collage of Pharmacy Jinan University Guangzhou China Key Laboratory of Cardiovascular Medicine Research Ministry of Education Harbin Medical University Harbin China Department of Chemistry University of Hong Kong Hong Kong Chian

OBJECTIVE To identify the specific targets of a novel derivative of Danshensu adtm as the protein disulfide isomerase(PDI)family proteins including *** further investigate the underlying mechanism of adtm to modulate ERp57 to regulate platelet function with direct interaction withαⅡbβ3 *** To isolate the protein targets that bound to adtm,a biotin-conjugated adtm analogue(BAA)was designed and ***(300μmol·L-1)was incubated with rat blood platelet lysates and the BAA-protein complexes were pulled down with NeutrAvidin-agarose followed by protein profiling using LC-MS/*** determine platelet aggregation in vitro,rabbit platelets were incubated with the indicated concentrations of compounds and aggregation was induced by ADP(10μmol·L-1)or AA(200μmol·L-1)and measured using a platelet *** determine platelet aggregation-induced by ADP in rat in vivo,adtm(5-20mg·kg-1)in comparison with DSS(10mg·kg-1)and clopidogrel(18mg·kg-1)were administered daily by *** for 5d,*** determine the action of adtm on the ERp57/αⅡbβ3 interaction,it was examined by immunoprecipitation with anti-αⅡbβ3antibody,followed by detection of ERp57 immunoreactivity using *** BAA could bind to various proteins involved in platelet *** particular,platelet aggregation-associated proteins were identified with>95% protein identification probability including ERp72,ERp57ERp5 and PDI,which are members of the protein disulfide isomerase(PDI)family related to platelet function and redox *** exhibited potent inhibition on the redox activity of ERp57 in a concentration-dependent manner(IC50=100 300μmol·L-1).In in vitro studies,adtm exhibited concentration-dependent inhibition on ADP-induced and AA-induced platelet aggregation with comparable effects to aspirin and *** vivo study showed that ADP-induced platelet aggregation was significantly compromised(>40%reduction)in rats treated with adtm(20mg·kg-1)

关键词： anti-platelet ERp57 Danshensu derivative adtm

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