Rashid Qudsia, Abid Mohammad, Gupta Neha, Tyagi Tarun, Ashraf Mohammad Z, Jairajpuri Mohamad Aman
Protein Conformation and Enzymology Lab, Department of Bio-Sciences, Jamia Millia Islamia (A Central University), Jamia Nagar, New Delhi 110 025, India.
Medicinal Chemistry Lab, Department of Biosciences, Jamia Millia Islamia, New Delhi 110 025, India.
Biomed Res Int. 2015;2015:630482. doi: 10.1155/2015/630482. Epub 2015 Mar 17.
Physiological hemostatic balance is a coordinated outcome of counteracting coagulation and fibrinolytic systems. An imbalance of procoagulant and anticoagulant factors may result in life threatening thromboembolism. Presently, anticoagulant administration is the first line of therapy for the treatment of these conditions and several anticoagulants have been approved, including various forms of heparin. However, the polyanionic nature and multispecificity of heparin pose several complications. Generally, the polysulfated compounds with antithrombotic potential are thought to have feasible synthetic procedures with much less bleeding, thus having favourable safety profiles. Here we report the synthesis of a novel compound, trehalose octasulfate and the assessment of its anticoagulation potential. Molecular docking of trehalose and trehalose octasulfate with antithrombin showed a specificity switch in binding affinity on sulfation, where trehalose octasulfate interacts with critical residues of AT that are either directly involved in heparin binding or in the conformational rearrangement of AT on heparin binding. An in vitro analysis of trehalose octasulfate demonstrated prolonged clotting time. Lead compound when intravenously injected in occlusion induced thrombotic rats showed remarkable reduction in the size and weight of the clot at a low dose. Delay in coagulation time was observed by analysing blood plasma isolated from rats preinjected with trehalose octasulfate. A decrease in Adenosine 5'-Diphosphate (ADP) induced platelet aggregation indicated a probable dual anticoagulant and antiplatelet mechanism of action. To summarize, this study presents trehalose octasulfate as a novel, effective, dual acting antithrombotic agent.
生理止血平衡是凝血系统与纤溶系统相互作用的协调结果。促凝因子和抗凝因子失衡可能导致危及生命的血栓栓塞。目前，抗凝药物治疗是这些疾病的一线治疗方法，几种抗凝剂已获批准，包括各种形式的肝素。然而，肝素的聚阴离子性质和多特异性会引发多种并发症。一般来说，具有抗血栓潜力的多硫酸化化合物被认为具有可行的合成方法，出血风险小得多，因此具有良好的安全性。在此，我们报告一种新型化合物——海藻糖八硫酸酯的合成及其抗凝潜力评估。海藻糖和海藻糖八硫酸酯与抗凝血酶的分子对接显示，硫酸化后结合亲和力发生特异性转变，其中海藻糖八硫酸酯与抗凝血酶的关键残基相互作用，这些残基要么直接参与肝素结合，要么参与抗凝血酶在肝素结合时的构象重排。对海藻糖八硫酸酯的体外分析表明其凝血时间延长。在闭塞诱导的血栓形成大鼠中静脉注射先导化合物，低剂量时即可显著减小血栓的大小和重量。分析预先注射海藻糖八硫酸酯的大鼠分离的血浆，观察到凝血时间延迟。5'-二磷酸腺苷（ADP）诱导的血小板聚集减少，表明其可能具有双重抗凝和抗血小板作用机制。总之，本研究将海藻糖八硫酸酯呈现为一种新型、有效、双效抗血栓药物。
