RATIONAL DESIGN OF ADHESION BLOCKING ANTIINFLAMMATORIES

该建议的目的是开发有效的选择配体类似物 以多价"阵列"形式存在，以抑制炎症驱动 病理性疾病有各种急性和慢性 可通过选择素阻断来预防或抑制的疾病 化合物.这些包括急性疾病，如缺血-再灌注 损伤、急性呼吸窘迫综合征、败血性休克， 多器官衰竭和慢性疾病包括过敏， 自身免疫、类风湿性关节炎、胰岛炎和糖尿病。在这 我们有两个具体目标。首先，我们将测量阻塞 一组确定的多聚化选择素配体类似物的效力 在UV交联稳定的脂质体上功能性表达。 这将 包括检查多聚化碳水化合物配体的作用 与多种"辅助"非碳水化合物改性剂组合， 将形成"表位阵列"。 通过这项研究，我们将制定一个 理解决定有效选择的因素 通过这些阵列的粘附阻断。 第二，我们将进行结构优化 最有效的抑制性选择素配体类似物 呈递的活性表位，活性和"辅助"配体的配制 组件和组件的整体尺寸。 这些阻塞 化合物和它们的改进将使用人类白细胞进行测试， 内皮滚动测定，然后在炎症动物模型中。 拟议的商业应用： 选择素阻断化合物的发现和成功构建 可以完全开发成强大的药物， 病理性炎症将在治疗这两种疾病方面具有巨大的价值。 急性和慢性人类疾病。 目前和预计估计数 表明有效抗炎产品具有广泛的疾病 应用可以代表超过十亿美元的产品市场。

The intent of this proposal is to develop potent selecting ligand analogs presented in multivalent "arrays" to suppress inflammation driven pathological disease. There are a variety of both acute and chronic diseases which may be prevented or suppressed by selectin blocking compounds. These include acute diseases such as ischemia-reperfusion injury, acute respiratory distress syndrome, septic shock leading to multiple organ failure and chronic diseases including allergy, autoimmunity, rheumatoid arthritis, insulitis and diabetes. In this proposal, we have two specific aims. First we will measure the blocking potency of a defined group of multimerized selectin ligand analogs functionally expressed on UV-cross-link-stabilized-liposomes. This will consist of examining the effects of multimerized carbohydrate ligands combined with a variety of "auxiliary" non-carbohydrate modifiers that will form "epitope arrays". Through this study, we will develop an understanding of factors responsible for determining effective selectin adhesion blocking by these arrays. Second, we will structurally optimize the most effective inhibitory selectin ligand analogs in terms of percent active epitopes presented, formulation of active and "assisting" ligand components and the overall size of the assembly. These blocking compounds and their refinements will be tested using human leukocyte- endothelial rolling assays and then in animal models of inflammation. PROPOSED COMMERCIAL APPLICATIONS: The discovery and successful construction of selectin blocking compounds that can he fully developed into powerful pharmaceuticals to blunt pathological inflammation will be of enormous value in treating both acute and chronic human disease. Current and projected estimates indicate that effective anti-inflammatory products with broad disease applications could represent more than a billion dollar product market.