Molecular interactions of marine carbohydrates and coagulation factors

海洋碳水化合物与凝血因子的分子相互作用

• 批准号: 10165751
• 负责人: Vitor Hugo Pomin
• 金额: $ 25.12万
• 依托单位: UNIVERSITY OF MISSISSIPPI
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-15 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10165751
• 关键词: Anticoagulants; Antithrombins; Attention; Basophils; Behavior; Binding; Biochemical Reaction; Biological Assay; Blood; Blood Coagulation Factor; Blood Platelets; Carbohydrates; Cardiovascular Diseases; Cardiovascular system; Cattle; Cause of Death; Centers of Research Excellence; Cessation of life; Chemical Structure; Chondroitin Sulfates; Clinic; Coagulation Process; Collection; Complex; Complex Analysis; Comprehension; Data; Deep Vein Thrombosis; Dermatan Sulfate; Disease; Docking; Dose; Echinodermata; Effectiveness; Europe; Exhibits; Family suidae; Fucose; Galactans; Galactose; Glycobiology; Glycosaminoglycans; Heart; Hemorrhage; Heparin; Heparin Cofactor II; Heparitin Sulfate; Heterogeneity; Holothuria; Human body; Hypotension; In Vitro; Injections; Investigation; Laboratories; Mass Fragmentography; Mediating; Medical; Mentors; Mexico; Mississippi; Molecular; Molecular Analysis; Myocardial Infarction; Myocardial Ischemia; Oligosaccharides; Pain; Pathology; Patients; Peptide Hydrolases; Pharmacology; Play; Polysaccharides; Property; Pulmonary Embolism; Rattus; Red Algae; Reporting; Research; Research Personnel; Risk; Sea Cucumbers; Sea Urchins; Sheep; Site; Source; Stroke; Structure; Sulfate; Symptoms; System; Techniques; Therapeutic Uses; Thrombin; Thrombocytopenia; Thromboembolism; Thrombosis; Time; Universities; Unstable angina; Venous Thrombosis; Weight; World Health Organization; analog; catalyst; chemical reaction; chemical synthesis; college; experience; fucoidan; in vivo; inhibitor/antagonist; marine organism; mast cell; novel; prevent; screening; side effect; sugar; tool; trend

Project 3: Molecular interactions of marine carbohydrates and coagulation factors Junior Investigator: Vitor Pomin Mentors: Ikhlas Khan, University of Mississippi & Barbara Mulloy, Imperial College Cardiovascular diseases are the major cause of deaths not only in the USA, but also worldwide. Heparin is the most commonly used therapeutic. However, this sulfated glycan (SG) presents serious drawbacks such as bleeding trends, thrombocytopenia and contamination risks. Therefore, novel antithrombotic SGs with unique structures and different mechanisms of actions have been recently discovered, especially those from marine organisms. For example, a sulfated galactan reported by our group, isolated from the red alga Botryocladia occidentalis, shows (a) nearly equal in vivo action of unfractionated heparin (UFH) in arterial thrombosis, (b) equal in vivo effect of UFH in venous thrombosis at low doses (below 0.25 mg/kg of rat weight), (c) no bleeding risk at 5 and 10 mg/kg of rat weight, as opposed to the high-hemorrhagic behavior of UFH at the same doses, and (d) an in vitro anticoagulant mechanism of action distinct from UFH, with greater activity mediated through heparin cofactor II (HCII) while still retaining some activity through antithrombin. The IC50 value of the HCII-mediated anti-IIa activity of B. occidentalis sulfated galactan was around twenty times more active than the one from natural catalyst of HCII, dermatan sulfate. In order to fully understand the underlying mechanisms of action of this new marine sugar in the coagulation system, we will investigate at the atomic level the resultant intermolecular complexes made by HCII and thrombin with an oligosaccharide of defined structure isolated from the B. occidentalis sulfated galactan. We will also isolate, characterize, and screen the in vitro anticoagulant and in vivo antithrombotic activities of new SGs extracted from echinoderms collected in the Gulf of Mexico which were not previously investigated. Our laboratory is experienced solving the structures of the marine SGs using NMR along with chemical reactions and assessing their effects as potential anticoagulants and antithrombotics. Our latest results have demonstrated key structural requirements, such as 2-sulfation at galactose units, 4-sulfation at fucose units and longer chains for the anticoagulant and antithrombotic activities of the sea urchin-derived SGs. The marine sugars can serve as useful molecular tools in investigations of the different mechanism of action of sulfated glycans in coagulation and thrombosis. In- depth comprehension about these novel mechanisms can also facilitate the potential exploration of the marine sugars in the cardiovascular therapy. This research not only will identify potential medicinal molecules and elucidate their properties, but the combination of its results will also help to push the current status-quo of marine glycobiology towards a new level.

项目3：海洋碳水化合物和凝血因子的分子相互作用 初级调查员：维托·波明 导师：密西西比大学Ikhlas Khan和帝国理工学院Barbara Mulloy 心血管疾病不仅在美国，而且在世界范围内都是主要的死亡原因。 肝素是最常用的治疗药物。然而，这种硫酸多糖(SG)表现出严重的 缺点，如出血趋势、血小板减少和污染风险。因此，小说 最近发现了具有独特结构和不同作用机制的抗血栓SGS， 尤其是那些来自海洋生物的生物。例如，我们小组报告的一种硫化半乳聚糖，从 结果表明：(A)普通肝素(UFH)在体内的作用与普通肝素(UFH)相当。 动脉血栓形成，(B)低剂量(低于0.25 mg/kg大鼠)UFH对静脉血栓形成的体内效应 体重)，(C)在5毫克/公斤和10毫克/公斤的老鼠体重下没有出血风险，而不是 相同剂量的UFH，以及(D)不同于UFH的体外抗凝作用机制， 通过肝素辅因子II(HCII)介导的活性，同时仍通过抗凝血酶保持一定的活性。这个 西瓜硫酸酯半乳聚糖对HCII介导的抗IIa活性的IC50值约为20倍。 比盐酸天然催化剂硫酸皮肤素的活性更高。为了充分理解 这种新的海洋糖在凝血系统中的潜在作用机制，我们将在 在原子水平上，由HCII和凝血酶与低聚糖形成的分子间络合物 从西方乳杆菌硫化半乳聚糖中分离得到确定的结构。我们还将分离、表征和 棘皮新提取物SGS体外抗凝活性和体内抗血栓活性的筛选 在墨西哥湾收集的，以前没有调查过的。我们的实验室有解决问题的经验 利用核磁共振和化学反应对海洋SGS的结构进行了研究，并对其影响进行了如下评估 潜在的抗凝血剂和抗血栓药。我们的最新结果显示了关键的结构要求， 例如半乳糖单元上的2-硫化、岩藻糖单元上的4-硫化和更长的抗凝血剂链以及 海胆提取物SGS的抗血栓活性。海洋糖可以作为有用的分子工具 研究硫酸葡聚糖在凝血和血栓形成中的不同作用机制。在- 对这些新机制的深入理解也有助于对海洋的潜在探索 心血管治疗中的糖类。这项研究不仅将识别潜在的药物分子和 阐明它们的性质，但其结果的结合也将有助于推动目前的现状 海洋糖生物学迈向新水平。