Cell-Based Screen-Inhibitors of Mucin-Type O-Linked(RMI)

描述(由申请人提供)：项目摘要：本提案的目标是开发高通量的基于细胞的分析方法，用于鉴定粘蛋白O型连接的葡聚糖的小分子抑制剂。粘蛋白O型连接的多糖结构在炎症和肿瘤转移中起着关键作用；然而，没有小分子、非碳水化合物的抑制剂被发现。本文描述的基于细胞的分析方法能够发现合成粘蛋白O型连接的多聚糖所需的任何生物合成酶的抑制剂。O-连接的葡聚糖生物合成酶的抑制剂将是探索这类碳水化合物生物学作用的有力研究工具。此外，抑制剂将是开发治疗癌症、炎症性疾病以及由流感和幽门螺杆菌引起的感染的疗法的起点。相关性：碳水化合物在许多人类疾病中扮演着重要的角色；然而，针对这类分子的药物普遍缺乏。这项建议旨在通过开发高通量筛选系统来确定一类特定类型的细胞表面碳水化合物的小分子抑制剂，即粘蛋白O型连接的多糖，以解决这一问题。通过这里提出的方法确定的小分子将作为研究工具和开发用于治疗癌症和传染病的新型药物的起点具有价值。

DESCRIPTION (provided by applicant): Project Summary: The goal of this proposal is to develop high throughput cell-based assays for the identification of small molecule inhibitors of mucin-type O-linked glycans. Mucin-type O-linked glycan structures play critical roles in inflammation and tumor metastasis; however, no small molecule, non carbohydrate inhibitors have been identified. The cell-based assays described herein have the ability to discover inhibitors of any biosynthetic enzyme required for the synthesis of mucin-type O linked glycans. Inhibitors of O-linked glycan biosynthetic enzymes would be powerful research tools to probe the biological roles of this class of carbohydrates. Furthermore, inhibitors would be starting points to develop therapeutics for treating cancer, inflammatory diseases, and infection caused by influenza and Helicobacter pylori. Relevance: Carbohydrates play essential roles in many human diseases; however, drugs targeting this class of molecules are generally lacking. This proposal aims to solve this problem by developing a high throughput screening system to identify small molecule inhibitors of a specific class of cell surface carbohydrates known as mucin-type O-linked glycans. Small molecules identified by the methods proposed here would have value as research tools and as the starting point to develop a new class of Pharmaceuticals for treating cancer and infectious diseases.