In vitro synthesis of recombinant heparan sulfate

描述（由申请方提供）：该提案旨在改善低分子量肝素（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（北卡罗来纳州大学）、罗伯特·林哈特博士（伦斯勒理工学院）、爱德华·哈里斯博士（内布拉斯加大学，林肯）和贾韦德·法里德博士（洛约拉大学医学中心）。LWMH是一种广泛用于治疗血栓性疾病的抗凝药物。目前市售的LMWH药物是硫酸化聚-/寡聚-葡聚糖的混合物，其易受污染和批次间变异性的影响。我们计划合成结构均匀的LMWH以消除结构异质性。新的LMWH构建体应显示出一致的抗凝活性，对鱼精蛋白中和的敏感性提高，以及受控的代谢途径。均质LMWH的合成将使用化学酶法完成。将在小鼠和灵长类动物模型中评价产品的药理学作用。该项目的成功将优化肝素类药物的结构，提高其安全性和有效性。

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.