基于毛细管电泳质谱联用技术(CE-MS)的非抗凝肝素序列解析及其抗炎构效关系研究

批准号:
82003708
项目类别:
青年科学基金项目
资助金额:
24.0 万元
负责人:
欧阳艺兰
依托单位:
学科分类:
药物分析
结题年份:
2023
批准年份:
2020
项目状态:
已结题
项目参与者:
欧阳艺兰
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中文摘要
肝素是从动物组织中提取的天然糖胺聚糖,是一类广泛应用于临床的抗凝药物。同时,肝素类药物除了抗凝外,还表现出了良好的抗炎作用,而高剂量抗凝肝素在抗炎过程中又无法避免出血风险。因此探索部分或者彻底清除抗凝片段的“非抗凝肝素”与抗炎活性之间的构效关系研究将十分必要。然而,肝素类药物有着复杂的结构。在改造肝素抗凝结构域进而制备“非抗凝肝素”的过程中引入了新的结构特征,进一步增加了这类物质结构的复杂性。这些极大地限制了“非抗凝肝素”抗炎构效关系研究。该课题将基于等电点聚焦毛细管电泳和电驱动鞘流液辅助电离的外置离子源CE-MS分析方法建立作为突破口,之后利用该分析平台揭示不同程度去抗凝活性、不同分子量大小、不同糖链组成和硫酸根分布的非抗凝肝素在抗炎活性上的差异。这些工作将为非抗凝肝素的新药开发与临床适应症的拓展提供积极的研发思路和有力的技术支持。
英文摘要
Heparin, an anticoagulant drug used widely in clinic, is a naturally polysaccharide belonging to the family of glycosaminoglycans and purified from animal tissue. While heparin has been used almost exclusively as a blood anticoagulant, important research demonstrates that it also has broad anti-inflammatory activity. However, high dose of anticoagulant heparins used in anti-inflammatory greatly increases bleeding risk. Therefore, it is necessary to explore the structure-activity relationship between partly or completely anticoagulant domain removed non-anticoagulant heparins and inflammatory. Heparin drugs are complex micro-heterogenous mixtures, in addition, modification of heparin anticoagulant domain induces new structural features and increases the structural complexity of the mixtures in further, which greatly limit study on structure-activity relationship in Anti-inflammatory. In our research, capillary isoelectric focusing method using an electrokinetically pumped sheath liquid nano-spray capillary electrophoresis-mass spectrometry (CE-MS) coupling technology will be established. The analysis platform helps to reveal how the structural features of non-anticoagulant heparins such as molecular weight, degree of anticoagulant activity, compositions, sulfo-location and number works on anti-inflammatory activity. This work will provide positive idea and strong technical support for the development of non-anticoagulant heparin as new drugs and the expansion of clinical indications.
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DOI:10.1021/acs.analchem.2c01579
发表时间:2022-09-14
期刊:ANALYTICAL CHEMISTRY
影响因子:7.4
作者:Yan,Na;Song,Feifan;Zhang,Zhenqing
通讯作者:Zhang,Zhenqing
国内基金
海外基金
