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: 10392500
• 负责人: Vitor Hugo Pomin
• 金额: $ 25.07万
• 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/10392500
• 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; Fibrinolytic Agents; 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; 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结因子的分子相互作用 初级调查员：Vitor Pomin 导师：密西西比大学和芭芭拉·穆洛伊大学伊克拉斯·汗（Ikhlas Khan），帝国学院 心血管疾病不仅在美国，而且是全球范围内的死亡原因。 肝素是最常用的治疗性。但是，这种硫酸化的聚糖（SG）呈现严重 诸如出血趋势，血小板减少症和污染风险等缺点。因此，新颖 最近已经发现了具有独特结构和不同作用机制的抗血栓形成SG， 特别是来自海洋生物的人。例如，我们的组报告的硫酸星酰胺从中分离出来 红色藻类葡萄糖层西方人，显示（a）几乎相等的体内肝素（UFH）在 动脉血栓形成，（b）在低剂量下，UFH在静脉血栓形成中的体内效应相等（低于0.25 mg/kg大鼠 重量），（c）在5和10 mg/kg的大鼠体重下没有出血风险 UFH以相同的剂量和（d）与UFH不同的体外抗凝作用机理，更大 通过肝素辅因子II（HCII）介导的活性，同时仍通过抗凝血酶保留一些活性。这 西方硫酸芽​​孢杆菌硫化银河的HCII介导的抗IIA活性的IC50值约为二十倍 比来自HCII的天然催化剂，硫酸皮肤化的天然催化剂更活跃。为了完全了解 这种新的海洋糖在凝血系统中的基本作用机制，我们将在 原子水平由HCII和凝血酶与寡糖产生的分子间复合物 从西卡氏芽孢杆菌硫化的银河系分离的定义结构。我们还将隔离，特征和 筛选从棘皮动物中提取的新SG的体外抗凝剂和体内抗血栓形成活性 在墨西哥湾收集，以前没有研究过。我们的实验室经验丰富 使用NMR以及化学反应的海洋SGS结构，并将其影响评估为 潜在的抗凝剂和抗肉眼药。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-硫酸化以及抗凝剂和较长的链条 海胆衍生的SGS的抗血栓性活动。海洋糖可以用作有用的分子工具 在研究硫化聚糖在凝血和血栓形成中的不同作用机理中。在- 对这些新型机制的深度理解也可以促进海军陆战队的潜在探索 心血管疗法中的糖。这项研究不仅会识别潜在的药用分子，并且 阐明其特性，但其结果的组合也将有助于推动当前状态 海洋糖生物学朝着新的水平迈进。