INHIBITORS OF GLYCOSYLTRANSFERASES

糖基转移酶抑制剂

• 批准号: 3195085
• 负责人: OLE HINDSGAUL
• 金额: $ 7.43万
• 依托单位: UNIVERSITY OF ALBERTA
• 依托单位国家: 美国
• 财政年份: 1989
• 资助国家: 美国
• 起止时间: 1989-09-01 至 1992-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3195085
• 关键词: CD antigens; N acetylglucosamine; carbohydrate biosynthesis; cell membrane; chemical structure function; chemical synthesis; enzyme inhibitors; enzyme substrate; enzyme substrate analog; fucose; glycosyltransferase; neoplastic transformation; oligosaccharides; tissue /cell culture; tumor antigens

The surface of animal cells is coated with carbohydrate structures whose functions remain very poorly understood. k has been widely observed, however, that these oligosaccharide structures change in a systematic way during cellular development including embryogenisis and tumor-progression. The new carbohydrate structures that appear during these processes are referred to as differentiation antigens or tumor-associated antigens. It has been postulated that these new structures mediate cell-cell recognition or adhesion. The biosynthesis of these cell-surface carbohydrate structures is mediated by enzymes termed glycosyltransferases. If these enzymes could be inhibited in a specific manner, then the expression of cell-surface carbohydrates could be precisely controlled Should certain oligosaccharides provide growth advantages to tumor-cells, as has been proposed, then inhibition of their biosynthesis would negate these advantages and possibly lead to a new mode of cancer therapy. In this proposal, 4 glycosyltransferases implicated in the production of aberrant cell-surface carbohydrates have been selected as targets for inhibition. For each of these enzymes, a specific substrate will be defined and analogs of this substrate, which cannot be acted on by the enzyme, will be chemically synthesized. These analogs are predicted to be specific inhibitors and they will be prepared in a form that should allow their entry into cells in order to access the target enzymes. If successful, the ability to change the cell surface carbohydrate structures would be in hand, as would the ability to control their function.

动物细胞表面覆盖有碳水化合物结构，其 功能仍然知之甚少。 k 已被广泛观察到， 然而，这些寡糖结构会以系统的方式发生变化 在细胞发育过程中，包括胚胎发生和肿瘤进展。 在这些过程中出现的新碳水化合物结构是 称为分化抗原或肿瘤相关抗原。它 假设这些新结构介导细胞间识别 或粘附。 这些细胞表面碳水化合物结构的生物合成是介导的 通过称为糖基转移酶的酶。如果这些酶可以被抑制 以特定的方式，然后表达细胞表面碳水化合物 可以精确控制 如果某些寡糖提供 正如已经提出的那样，对肿瘤细胞的生长有利，然后抑制 它们的生物合成将抵消这些优势并可能导致新的 癌症治疗的模式。 在该提案中，涉及 4 种糖基转移酶的生产 异常的细胞表面碳水化合物已被选为目标 抑制。对于每种酶，都会定义特定的底物 和该底物的类似物，不能被酶作用，将 可以化学合成。这些类似物预计具有特异性 抑制剂，并且它们将以允许其 进入细胞以获得目标酶。如果成功的话， 改变细胞表面碳水化合物结构的能力 手，以及控制其功能的能力。