以细胞膜磷脂酰丝氨酸为靶点的生物药物的发现、功能及优化改造

Membrane phosphatidylserine (PS) is tightly associated with many diseases. Members of Annexin family have the phospholipid-binding ability, displaying promising potential for drug discovery and development. There are 19 members or splicing alternatives in human annexin family, their functions still remain unclear. This proposal aims to systematically investigate the relationship between the structure and evolution, function of each individual member of human annexin family, and to screen and discover biologic candidates with well efficacy and less toxic effect, by targeting at phosphatidylserine. . This proposal will reveal the relationship between the protein structure and efficacy, toxicity of annexin family members and the underlying mechanisms. Based on the analyses and knowledge obtained from the above studies and relied on the approaches of structural optimization, molecular design and protein engineering, this proposal aims to develop innovative biopharmaceutical, targeting phosphatidylserine, with higher biological activities and efficacy, and better safety. . The present research team has been long-timely devoted to the structural and functional relationship study of Annexin family, mainly focused on annexin V, and the development of innovative new drug from annexins. We have already published 34 research articles, among which 16 papers appeared in SCI journals, produced from our previous studies on the structure-function-toxicity relationship of annexin V.. From the studies on annexin V, we have gotten 7 patent authorizations from China, American and Europe. 5 patent applications under review. Two innovative biopharmaceuticals derived from annexin V have finished all the preclinical studies and ready for clinic trail application.

细胞膜磷脂酰丝氨酸PS与许多重要疾病密切相关，膜联蛋白Anx成员与细胞膜磷脂酰丝氨酸PS结合，具有良好的药物发现价值和新药研发前景。人类Anx家族成员及其剪切体多达19个，其生物学功能尚不清楚。. 本项目拟系统性地深入剖析人Anx家族各成员的结构与其进化和功能的关系；从中筛选并发现以PS为靶点的、具有较好药效学作用和低毒副作用的Anx类候选药物；将揭示人Anx蛋白质结构与其药效、毒副作用的关系及其机制，在此基础上通过结构优化和蛋白质工程改造，研制以磷脂酰丝氨酸为靶点，性能更好、安全性更佳的原创生物药物。本课题组长期从事Anx家族（尤其是AnxV）的结构与功能关系及其创新药物研究，前期已经围绕AnxV结构与功能及毒性的关系，发表研究论文34篇，含SCI论文16篇，已获AnxV相关中、美、欧盟发明专利7件，申请发明专利5件，2个AnxV衍生创新生物药物已经转让企业，并已完成临床前研究。

细胞膜磷脂酰丝氨酸PS与许多重要疾病密切相关，膜联蛋白Annexin成员与细胞膜磷脂酰丝氨酸PS结合，具有良好的药物发现价值和新药研发前景。人类Annexin家族成员及其剪切体多达19个，其生物学功能尚不清楚。本项目开展细胞膜磷脂酰丝氨酸(PS)为靶点的候选生物药物研究，完成了计划书预定的研究内容和研究目标。系统性分析了人Annexin家族成员的结构与生物学功能、尤其是与其细胞膜PS亲和力的关系；获得了Anx V的4个突变体的6个晶体结构；深入研究了Anx V的结构及其磷酸化修饰与其生物学功能、药效学作用及其分布代谢的关系；阐明了AnxV对多种疾病的治疗作用及其机制，发现PS是炎症性肠病的治疗靶点、AnxV具有治疗炎症性肠病的作用；阐明Anx10在转移性黑色素瘤中的作用、机制及临床意义。研发的AnxV变体新药基本完成临床前研究；研发了富含Ca-PS脂质体的新转染试剂，提高了原代免疫细胞的转染效率；发展了简易的基于分光光度计的细胞凋亡检测新方法；研究了不同类型抗肿瘤药物及治疗方法下，不同类型肿瘤产生细胞凋亡和细胞膜PS的变化与治疗疗效和预后的关系。本项目在国内外核心期刊发表文章50篇；获中国发明专利5件，美国发明专利1件，申请中国发明专利4件、PCT国际专利1件；2件发明专利分别获中国专利优秀奖、常州市专利优秀奖；获江苏省科学技术奖一等奖、高等学校科学研究优秀成果奖（科学技术）技术发明一等奖各1项。参与本项目研究的研究生获中国“互联网+”大学生创新创业大赛金奖、“挑战杯”中国大学生创业计划竞赛全国决赛金奖、“i创达人”科技创新创业计划大赛全国总决赛亚军等8项荣誉；参与本项目研究的英才计划中学生分别获江苏省青少年科技创新大赛一等奖3项、二等奖2项等全国及省市级奖励7项。