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 初级研究者：Vitor Pomin 导师：密西西比大学的Ikhlas Khan和帝国理工学院的Barbara Mulloy 心血管疾病不仅在美国，而且在全世界都是死亡的主要原因。 肝素是最常用的治疗药物。然而，这种硫酸化聚糖（SG）呈现严重的 缺点如出血趋势、血小板减少症和污染风险。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形成SG， 尤其是来自海洋生物的。例如，我们小组报告的一种硫酸化半乳聚糖，从 红葡萄枝藻，显示（a）在体内几乎与普通肝素（UFH）相同的作用， 动脉血栓形成，（B）低剂量（低于0.25 mg/kg大鼠）的UFH在静脉血栓形成中的体内作用相等 （c）在5和10 mg/kg大鼠体重时无出血风险，而在10 mg/kg大鼠体重时无高出血行为。 （d）与UFH不同的体外抗凝作用机制， 通过肝素辅因子II（HCII）介导的活性，同时通过抗凝血酶仍保留一些活性。的 HCII介导的B抗IIa活性的IC 50值。硫酸化半乳聚糖是 比天然的HCII催化剂硫酸皮肤素活性更高。为全面了解 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和凝血酶与以下寡糖形成的所得分子间复合物 与B分离的明确结构。硫酸半乳聚糖我们还将分离，表征， 筛选从棘皮动物中提取的新SG的体外抗凝和体内抗血栓活性 在墨西哥湾收集的，以前没有调查过。我们的实验室有经验解决 利用核磁共振沿着化学反应来研究海洋SG的结构，并评估它们的作用， 潜在的抗凝剂和抗血栓剂。我们的最新结果表明了关键的结构要求， 例如半乳糖单元的2-硫酸化、岩藻糖单元的4-硫酸化和抗凝剂的长链， 海胆衍生SG的抗血栓形成活性。海洋糖可以作为有用的分子工具 研究硫酸化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 糖在心血管治疗中的作用这项研究不仅将确定潜在的药物分子， 阐明其性质，但其结果的组合也将有助于推动目前的现状， 海洋糖生物学迈向新水平。