In vitro synthesis of recombinant heparan sulfate

重组硫酸乙酰肝素的体外合成

• 批准号: 8711536
• 负责人: JIAN LIU
• 金额: $ 37.48万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-02-13 至 2017-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8711536
• 关键词: Academic Medical Centers; Animals; Anticoagulants; Antithrombins; Binding Sites; Biochemical; Biochemistry; Biological Testing; Blood coagulation; Carbohydrates; Chemicals; Data; Disaccharides; Disease; Dose; Enoxaparin; Enzymes; Evaluation; Family; Figs - dietary; Funding; Hemorrhage; Heparin; Heparitin Sulfate; Heterogeneity; Human; Iduronic Acid; In Vitro; Inorganic Sulfates; Institutes; Jaw; Low-Molecular-Weight Heparin; Mammalian Cell; Marketing; Metabolic Clearance Rate; Metabolic Pathway; Methods; Modeling; Modification; Mus; Nebraska; North Carolina; Oligonucleotides; Oligosaccharides; Osteoporosis; Patients; Pharmaceutical Preparations; Pharmacology; Polysaccharides; Predisposition; Primates; Property; Protamines; Reaction; Recombinants; Reducing Agents; Research; Risk; Safety; Series; Side; Structure; Substrate Specificity; Surface; Thrombosis; Universities; Unspecified or Sulfate Ion Sulfates; animal tissue; base; design; epimerase; fondaparinux; high risk; improved; liver metabolism; member; next generation; pharmacophore; prophylactic; public health relevance; success; tool

DESCRIPTION (provided by applicant): The proposal is aimed to improve the pharmacological effects of low-molecular weight heparins (LMWH). This project is a collaborative effort of four research groups, including Dr. Jian Liu (University of North Carolina) Dr. Robert Linhardt (Rensselaer Polytechnic Institute), Dr. Edward Harris (University of Nebraska, Lincoln) and Dr. Jawed Fareed (Loyola University Medical Center). LWMH is a widely used anticoagulant drug to treat thrombotic disorders. The currently marketed LMWH drugs are a mixture of sulfated poly-/oligo-saccharides, which are vulnerable to contamination and batch-to-batch variability. We plan to synthesize structurally homogeneous LMWH to eliminate the structural heterogeneity. The new LMWH constructs should display consistent anticoagulant activity, improved sensitivity to protamine neutralization, and controlled metabolic pathway. The synthesis of homogeneous LMWH will be completed using a chemo enzymatic approach. The pharmacological effects of the products will be evaluated in mouse and primate models. The success of this project will optimize the structures of heparin-based drugs with improved safety and efficacy.

描述（由申请人提供）：该提案旨在提高低分子量肝素（LMWH）的药理作用。该项目是四个研究小组的合作成果，包括刘健博士（北卡罗来纳大学）、Robert Linhardt博士（伦斯勒理工学院）、Edward Harris博士（内布拉斯加州大学林肯分校）和Jawed Fareed博士（洛约拉大学医学中心）。LWMH是一种广泛应用于治疗血栓性疾病的抗凝药物。目前市场上销售的低分子肝素药物是硫酸化的多/寡糖混合物，容易受到污染和批次间的可变性。我们计划合成结构均匀的低分子肝素，以消除结构不均匀性。新的低分子肝素结构应该具有一致的抗凝血活性，提高对鱼精蛋白中和的敏感性，并控制代谢途径。均相低分子肝素的合成将采用化学酶法完成。产品的药理作用将在小鼠和灵长类动物模型中进行评估。该项目的成功将优化肝素类药物的结构，提高安全性和有效性。