In vitro synthesis of recombinant heparan sulfate

描述(申请人提供)：该提案旨在提高低分子肝素(LMWH)的药理作用。该项目是四个研究小组的共同努力，包括北卡罗来纳大学的刘健博士、伦斯勒理工学院的罗伯特·林哈特博士、内布拉斯加大学林肯分校的爱德华·哈里斯博士和洛约拉大学医学中心的Jawed Fareed博士。低分子肝素是一种广泛使用的抗凝药物，用于治疗血栓性疾病。目前上市的低分子肝素药物是硫酸盐多糖/低聚糖的混合物，容易受到污染和批次之间的变异性。我们计划合成结构均一的LMWH，以消除结构的异质性。新的低分子肝素构建物应该具有一致的抗凝活性，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使用化学酶法来完成。这些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以肝素为基础的药物的结构，提高安全性和有效性。

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.