蛋白质二硫键异构酶ERp57抑制剂的发现及其抗血栓活性研究

项目名称： 蛋白质二硫键异构酶ERp57抑制剂的发现及其抗血栓活性研究

项目编号： No.81460552

项目类型： 地区科学基金项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 崔国祯

作者单位： 遵义医科大学

项目金额： 48万元

中文摘要： 血栓性疾病是威胁人类健康的常见病。然而，目前血栓性疾病的治疗药物都存在不同程度的毒副作用。针对新靶标研制抗血栓新药，是应对血栓性疾病的有效手段。最近文献报道了二硫键异构酶ERp57是抗血栓的潜在药靶，但目前尚无ERp57特异性抑制剂的报道。因此，发现可拮抗ERp57酶活性的先导化合物，阐明其抗血栓机制对抗血栓新药的研发尤为重要。本项目组前期报道了新型化合物ADTM具有心肌保护作用，还发现该化合物可与ERp57蛋白结合并抑制其酶活性，具有较强的抗血小板聚集和抗血栓活性。本课题在前期创新性结果的基础上，拟解析该化合物和ERp57蛋白复合物的晶体结构，综合应用计算虚拟筛选等手段，以期发现活性更高的ERp57抑制剂、评价其抗血小板聚集和抗血栓的活性并探讨其作用机制。本课题将确证ERp57这一抗血栓的新靶点、首获高活性的ERp57小分子抑制剂、并评价成为抗血栓药物先导化合物的可能性。

中文关键词： 蛋白质二硫键异构酶ERp57；抗血栓；抑制剂；靶点；丹参素川芎嗪衍生物

英文摘要： Thrombotic disease is a common critical event that causes life-threatening health condition in human. The current antiplalate drugs, such as aspirin and clopidogrel, effectively reduce the risk of thrombus formation to human, unfortunatley, no pharmacological responses exsit in some cases, and what's wores is that the drugs increase incidence of major hemorrhage and other unwanted side effects. There is a great need for the improvement of existing therapeutic agents and development of new ones for the prevention and treatment of thrombotic disease. New antithrombotic agents targeted novel proteins with improved efficacy and free of the side effects are necessary to be developed to address the current unmet needs. In the recent days, it is reported that the disulfide isomerase ERp57 is a potential target for the treatment antithrombotic therapy. The ideal inhibotor targeting ERp57 has yet to be developed. There are an increasing number of compounds in drug development trace their origins back to structure based drug design. In this project, we previously reported a novel compound, named ADTM, which was synthesized by modifying a heterodimer of Danshensu and chuanxiongqin, exhibited strong cardioprotective effects in vitro and in vivo. In addition, using chemical proteomic approach, we found that ADTM targets ERp57 and displays antiplatelet and antithrombotic effects. In the recent times, computor aided drug design strateries have been used successfully in drug design and protein inhibitor development processes. The current our new findings and relevant research literature provide important evidences for further development of ADTM analogues as a novel target-based anti-thrombotic agent. The crystal structure of human ERp57 ligand-binding domain bound to ADTM will be clarified. The high resolution insights into ERp57 and ADTM complex structure will enable the application of structure based virtual screening to develop better ERp57 chemical inhibitors for the treatment of thrombotic desease. A pharmacophore model for binding of ADTM to ERp57 will be derived. We proposed that the new ERp57 inhibitor with more inhibitory effects than ADTM will be found based upon the pharmacophore searching. Nest, the effects of the new coumpounds with effectively inhibitory effeficary to ERp57 on platelet aggregation and thrombotic formation will be evaluated. Finally, the novel small molelcules, highly effective inhibitors of ERp57 can be easy to synthesized, were found and were further evaluated to expore its possibility to be a promising lead candidate for the treatment of thrombotic desease.

英文关键词： protein disulfide isomerase ERp57;anti-thrombosis;inhibitor;target;Danshensu chuanxiongqin derivative