Development of a New Carbohydrate-based Anticoagulant Drug

低分子肝素(LMWHs)是医院常用的抗凝药物。 碳水化合物分子。肝素是通过长期和不可靠的供应从猪肠中分离出来的 链条。低分子肝素是肝素的解聚产物。受污染的肝素在全球的分布 2007年，影响低分子肝素的纯度和安全性的事件在美国导致了85人死亡。这场危机 揭示了低分子肝素供应链对掺假的脆弱性。就在最近，美国国会表示， 对肝素供应链安全性的担忧，并敦促美国食品和药物管理局增加 消除污染和掺假风险的努力。加强对产品质量控制的监督 如果突然中断，动物来源的肝素不会成为这种救命药物的替代来源 肝素供应链的问题发生了。消除与动物有关的问题的一个最终解决方案- 来源肝素是开发一种低成本制备合成肝素的方法。 低分子量氢化合物是一种复杂的混合物，平均分子质量为3500-6000道尔顿，相应 至12-20个糖类单位。合成低分子肝素的高效制备可提高其安全性、可用性 和药效。然而，由于存在困难，均质低分子肝素的生产一直不可能。 化学合成。葡聚糖治疗公司建议评估一种创新的化学酶疗法， 将在肝素的制备中提供前所未有的效率。我们的产品将不含动物， 结构均一，对肾功能受损患者安全，并具有抗凝血活性 被鱼精蛋白中和。为了展示可伸缩性，一种新的合成低分子肝素的克级合成 建造工作已经完成。人工合成低分子肝素的一系列生物学、药理和毒性研究 都是为了证明进一步的发展是合理的。在建议进行的第一期沙田至中环研究中，我们会评估 中试规模合成的可行性(20克)和产品的纯度。目标1将开发可扩展的 方法合成2个糖核苷酸辅因子和1个磺基供体辅因子。Aim 2将演示 合成20克规模的低分子肝素的合成。在第二期工程研究中，我们计划 优化生产方案，将合成规模扩大到200克，以实现毒理学和抗凝血剂功效 通过学习获得工商管理硕士学位。该项目的建成将使这一百年老药以更先进的技术实现现代化 安全性和抗凝血性。

Low molecular weight heparins (LMWHs), a commonly used anticoagulant drug in the hospitals, are carbohydrate-based molecules. Heparin is isolated from porcine intestine through a long and unreliable supply chain. LMWH is a depolymerized product of heparin. A worldwide distribution of contaminated heparin in 2007, impacting the purity and safety of LMWHs, was associated with 85 deaths in the US. This crisis revealed the vulnerability of the LMWH supply chain to adulteration. Very recently, US congress expressed concerns over the safety of heparin supply chains and urged US Food and Drug Administration to increases the efforts to eliminate the risk of contamination and adulteration. Increasing oversight on the quality control of animal-sourced heparin does not provide an alternative source for this life-saving drug if a sudden interruption of heparin supply chain happens. One ultimate solution to eliminate the problems associated with the animal- sourced heparin is to develop a cost-effective method to prepare synthetic heparin. LMWHs are complex mixtures, having average molecular masses of 3500-6000 Daltons, corresponding to 12-20 saccharide units. The efficient preparation of a synthetic LMWH could improve the safety, availability and efficacy. However, the production of homogeneous LMWHs has not been possible due to difficulties in the chemical synthesis. Glycan Therapeutics proposes to assess an innovative chemoenzymatic approach that would provide an unprecedented efficiency in the preparation of heparin. Our product will be animal-free, structurally homogenous, safe for renal-impaired patients, and have the ability of its anticoagulant activity to be neutralized by protamine. To demonstrate the scalability, a gram-scale synthesis of a new synthetic LMWH construct was completed. A series of biological, pharmacological and toxicity studies of the synthetic LMWH were conducted to justify further development. In the Phase I STTR studies proposed here, we will assess the feasibility of a pilot scale synthesis (20 grams) and the purity of the product. Aim 1 will develop scalable methods to synthesize two sugar nucleotide cofactors and one sulfo donor cofactor. Aim 2 will demonstrate the synthesis of a synthetic LMWH construct in the scale of 20 grams. In the Phase II STTR studies, we plan to optimize production protocols to scale synthesis to 200 grams for toxicology and anticoagulant efficacy studies leading to an IND. The completion of this project will modernize this century-old drug with improved safety and anticoagulant properties.