PROTAMINE HYPERSENSITIVITY AND POLYON BIOLOGY

鱼精蛋白过敏和 Polyon 生物学

• 批准号: 3133320
• 负责人: John M Weiler
• 金额: $ 18.56万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 1985
• 资助国家: 美国
• 起止时间: 1985-09-30 至 1993-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3133320
• 关键词: affinity chromatography; anticoagulants; chemical structure function; complement; complement inhibitors; complement pathway; delayed hypersensitivity; drug adverse effect; drug design /synthesis /production; drug hypersensitivity; eosinophil; gel electrophoresis; heart surgery; heparin; high performance liquid chromatography; human subject; immediate hypersensitivity; immunoglobulin E; immunoglobulin G; polysaccharides; protamines; protein sequence

Protamine sulfate, a strong polycation, is used extensively in clinical medicine to block anticoagulant activity to heparin, a strong polyanion. Recent studies indicate that protamine may be a major cause of morbidity and mortality in patients who undergo cardiopulmonary bypass and that these reactions are not predictable in most cases. Furthermore, new low molecular weight heparins may not be as easy to neutralize as commercial heparin. Therefore, a new agent is urgently needed, to replace protamine, to block the anticoagulant activity of heparin without itself having anticoagulant or procoagulant activity or capacity to cause Type I hypersensitivity or to act on complement. One major mechanism by which polyions exert activity in vivo appears to be through the complement system. These studies will investigate a variety of polyions for capacity to regulate complement using state-of- the-art assays (Section D.2). Polyanions (polydisperse heparin and monodisperse heparin oligosaccharides) will be examined in detail to determine the structure and activity relationship for activity on complement (Section D.3). Polycations will be studied to determine specific mechanisms by which these basic substances regulate complement and again to determine the structure and activity relationship (Section D.4). The mechanism by which polycations preferentially inhibit the classical and polyanions preferentially inhibit the alternative pathways of complement will be determined (Section D.5). Affinity chromatography will be combined with conventional chromatography to purify heparin oligosaccharides with high capacity to bind complement (Section D.6). These heparin oligosaccharides will be studies for binding affinity to protamine, complement and a variety of polycations (Section D.7). These investigations will also determine the sequences in Hep which have high affinity for C3 and the sequence in C3 to which Hep binds. These studies should provide a more complete understanding of the complex role that polyions play in regulating complement activity and could lead to the development of new pharmacological agents.

硫酸鱼精蛋白是一种强聚阳离子，广泛应用于临床 药物以肝素抗凝活性阻断，多阴离子性强。 最近的研究表明，鱼精蛋白可能是发病的主要原因 和死亡率， 这些反应在大多数情况下是不可预测的。 此外，New Low 分子量肝素可能不像市售肝素那样容易中和 肝素 因此，迫切需要一种新的药剂， 鱼精蛋白，以阻断肝素的抗凝活性， 具有抗凝血或促凝血活性或导致I型糖尿病的能力 超敏反应或作用于补体。 聚离子在体内发挥活性的一个主要机制似乎是， 通过补体系统。 这些研究将调查 各种聚离子的能力，以调节补体使用的状态- 最先进的试验（第D.2节）。 聚阴离子（多分散肝素和 单分散肝素低聚糖）将被详细检查， 确定活性的结构和活性关系 补体（第D.3节）。 将对聚阳离子进行研究，以确定 这些基本物质调节补体的特殊机制 并再次确定结构和活性关系（第 D. 4）。 聚阳离子优先抑制 经典和聚阴离子优先抑制替代途径 将确定补体的量（第D.5节）。 亲和层析 将与常规色谱法结合纯化肝素 具有高补体结合能力的寡糖（第D.6节）。 将研究这些肝素寡糖与 鱼精蛋白、补体和各种聚阳离子（第D.7节）。 这些 研究还将确定Hep中的序列， 对C3的亲和力和C3中Hep结合的序列。 这些研究 应该提供一个更完整的理解的复杂作用， 聚离子在调节补体活性中起作用，并可能导致 开发新的药物制剂。