Development of a New Carbohydrate-based Anticoagulant Drug

低分子量肝素（LMWH）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LMWH是肝素的解聚产物。受污染的肝素在全球范围内的分布， 2007年，影响LMWH的纯度和安全性，与美国85例死亡有关。这场危机 揭示了LMWH供应链对掺假的脆弱性。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 努力消除污染和掺假的风险。加强质量控制监督， 如果突然中断，动物源性肝素不能提供这种救命药物的替代来源 肝素供应链的问题一个最终的解决方案，以消除与动物有关的问题- 来源的肝素是开发一种成本有效的方法来制备合成肝素。 LMWH是复杂的混合物，具有3500-6000道尔顿的平均分子量，对应于 至12-20个糖单元。合成LMWH的有效制备可提高LMWH的安全性、有效性 和功效。然而，由于制备中的困难，不可能生产均匀的LMWH。 化学合成聚糖治疗公司建议评估一种创新的化学酶法， 将在肝素的制备中提供前所未有的效率。我们的产品不含动物成分 结构均匀，对肾损害患者安全，并具有抗凝活性， 被鱼精蛋白中和为了证明可扩展性，采用克级合成新的合成LMWH 建设已经完成。合成LMWH的一系列生物学、药理学和毒性研究 是为了证明进一步的发展。在此处建议的第一阶段STTR研究中，我们将评估 中试规模合成（20克）的可行性和产物的纯度。Aim 1将开发可扩展的 合成两种糖核苷酸辅因子和一种磺基供体辅因子的方法。目标2将展示 以20克的规模合成合成LMWH构建体。在II期STTR研究中，我们计划 优化生产方案，将合成规模扩大到200克，以获得毒理学和抗凝血功效 该项目的完成将使这种百年药物现代化， 安全性和抗凝特性。

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.