FUCOSYLTRANSFERASE INHIBITORS WITH THERAPEUTIC POTENTIAL

具有治疗潜力的岩藻糖基转移酶抑制剂

• 批准号: 6293157
• 负责人: John L. Magnani
• 金额: $ 10万
• 依托单位: GLYCOTECH CORPORATION
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-09-30 至 2002-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6293157
• 关键词: Golgi apparatus; N acetylglucosamine; antiinflammatory agents; antiulcer drug; bioengineering /biomedical engineering; biotechnology; carbohydrate structure; cell adhesion; cell line; diagnosis design /evaluation; drug design /synthesis /production; drug screening /evaluation; enzyme inhibitors; enzyme linked immunosorbent assay; enzyme therapy; flow cytometry; fluorescence microscopy; fucose; galactosyltransferases; glycoprotein biosynthesis; hexosyltransferase; membrane permeability; oligosaccharides; protein protein interaction; sialyltransferases

DESCRIPTION (applicant's abstract): Fucose-containing oligosaccharides are well documented to mediate important cell adhesion and cell communication events Including, trafficking of leukocytes, cancer metastasis, and host pathogen interactions. Blocking adhesion events involving fucosylated oligosaccharides represents a viable approach to the treatment of diverse indications such as chronic inflammatory disease and ulcers. One way to accomplish this is to prevent the synthesis of the carbohydrates themselves. A family of fucosyltransferases that are expressed in a tissue and cell type specific manner carries out attachment of fucose to carbohydrates. Thus, inhibition of a specific fucosyltransferase has the potential to be a highly selective method of disrupting cell adhesion events mediated by fucose containing carbohydrates. The proposed research is directed to characterizing the specificity and cell permeability of three new classes of fucosyltransferase inhibitors with in vitro IC50 values as low as 68 nM. Unlike previously reported inhibitors based on donor and acceptor substrates, they are uncharged, non-carbohydrate small molecule organic compounds. These inhibitors provide the basis for development of potent orally available fucosyltransferase inhibitors with potential for treatment of chronic inflammatory disease. PROPOSED COMMERCIAL APPLICATION: The fucosylated oligosaccharide sialyl-Lewis X is a key mediator of leukocyte trafficking in conditions of chronic inflammation. Thus, inhibitors of the fucosyltransferase FucT-VII are anticipated to be effective in treatment of chronic inflammatory conditions such as rheumatoid arthritis, multiple sclerosis and psoriasis. Each of these conditions comprises major unmet medical needs and has the potential for mufti-billion dollar markets.

描述（申请人摘要）：含岩藻糖的低聚糖 记录介导重要的细胞粘附和细胞通讯事件 包括白细胞的运输、癌症转移和宿主病原体 交互.岩藻糖基化低聚糖的粘附阻断作用 代表了治疗各种适应症的可行方法，例如 慢性炎性疾病和溃疡。实现这一点的一种方法是 阻止碳水化合物自身的合成。口之家 在组织和细胞类型特异性表达的岩藻糖基转移酶 方式进行岩藻糖与碳水化合物的连接。因此，抑制A 特异性岩藻糖基转移酶具有成为高选择性方法的潜力 破坏由含岩藻糖的碳水化合物介导的细胞粘附事件。 拟议的研究是针对表征的特异性和细胞 三种新型岩藻糖基转移酶抑制剂的渗透性 体外IC 50值低至68 nM。与以前报道的抑制剂不同， 在供体和受体底物上，它们是不带电的，非碳水化合物小分子， 分子有机化合物。这些抑制剂为发展提供了基础 有效的口服岩藻糖基转移酶抑制剂， 治疗慢性炎症性疾病。 拟定商业应用： 岩藻糖基化低聚糖唾液酸-路易斯X是慢性炎症条件下白细胞运输的关键介质。因此，预期岩藻糖基转移酶FucT-VII的抑制剂可有效治疗慢性炎性病症，例如类风湿性关节炎、多发性硬化和牛皮癣。这些疾病中的每一种都包括未得到满足的主要医疗需求，并具有数十亿美元的市场潜力。