Maddineni Jyothi, Ma Qing, Hoppensteadt Debra A, Demir Muzaffer, Manoni Marco, Cornelli Umberto, Fareed Jawed
Loyola University Medical Center, Thrombosis and Hemostasis Research Laboratories, Maywood, IL 60153, USA.
Clin Appl Thromb Hemost. 2004 Jan;10(1):27-37. doi: 10.1177/107602960401000105.
Low-molecular-weight heparins (LMWH) represent depolymerized porcine mucosal heparin derivatives, which are commonly used for the management of thrombotic disorders. Because of their widespread usage, the supplies of the raw material namely unfractionated heparin are nearly exhausted. Porcine mucosal tissue is almost exclusively used for the preparation of these agents. Thus, there is a timely need for the production of heparin like drugs from other sources. Fermentation techniques have been used to produce carbohydrates such as dextran and innulin for therapeutic purposes. Bacterial cell wall polysaccharide mimics the linear hexose units, which constitute heparin. Utilizing Escherichia coli cell membranes produced by fermentation technology, chemical sulfation and enzymatic epimerization, sulfaminoheparosan type of polymer mimicking the structure of heparin has been produced. These semi-synthetic sulfaminoheparosans exhibit biologic actions comparable to that observed with heparin. The sulfaminoheparosan core can also be degraded to obtain low-molecular-weight (LMW) derivatives mimicking LMWHs. Using this technique, a novel LMW sulfaminoheparosan derivative (Q93C/239) was produced by Inalco, Milan, Italy. To compare this heparin analogue, a LMWH, namely tinzaparin, was used to determine the relative anticoagulant, antiprotease, and molecular profile. Additional studies were carried out to determine the susceptibility of this agent to heparinase-I. These comparative studies exhibited both antiprotease and anticoagulant properties similar to those of tinzaparin. However LMW sulfaminoheparosan resisted heparinase-I digestion at low heparinase-I concentrations. These studies demonstrate that the sulfaminoheparosan derived LMW components exhibit similar molecular and anticoagulant profile as tinzaparin and warrant additional preclinical and clinical development to determine their potential usefulness as antithrombotic agents.
低分子量肝素（LMWH）是猪黏膜肝素的解聚衍生物，常用于治疗血栓性疾病。由于其广泛应用，原料即普通肝素的供应几乎枯竭。猪黏膜组织几乎专门用于制备这些药物。因此，迫切需要从其他来源生产类似肝素的药物。发酵技术已被用于生产用于治疗目的的碳水化合物，如右旋糖酐和菊粉。细菌细胞壁多糖模仿构成肝素的线性己糖单元。利用发酵技术生产的大肠杆菌细胞膜、化学硫酸化和酶促差向异构化，已生产出模仿肝素结构的类肝素硫酸乙酰肝素聚合物。这些半合成类肝素硫酸乙酰肝素表现出与肝素相当的生物学活性。类肝素硫酸乙酰肝素核心也可降解以获得模仿低分子量肝素的低分子量（LMW）衍生物。利用该技术，意大利米兰的Inalco公司生产了一种新型低分子量类肝素硫酸乙酰肝素衍生物（Q93C/239）。为了比较这种肝素类似物，使用了一种低分子量肝素即替扎肝素，以确定其相对抗凝、抗蛋白酶和分子特征。还进行了其他研究以确定该药物对肝素酶-I的敏感性。这些比较研究显示出与替扎肝素相似的抗蛋白酶和抗凝特性。然而，低分子量类肝素硫酸乙酰肝素在低肝素酶-I浓度下能抵抗肝素酶-I的消化。这些研究表明，类肝素硫酸乙酰肝素衍生的低分子量成分表现出与替扎肝素相似的分子和抗凝特征，值得进行更多的临床前和临床开发，以确定它们作为抗血栓药物的潜在用途。
