INHIBITION OF COMPLEX CARBOHYDRATE BIOSYNTHESIS

复杂碳水化合物生物合成的抑制

基本信息

批准号：
2756970
负责人：
BRUCE GANEM
金额：
$ 6.09万
依托单位：
CORNELL UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
1986
资助国家：
美国
起止时间：
1986-01-01 至 1999-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/2756970
关键词：
N acetylglucosaminidase O glycosidase antineoplastics antiviral agents calnexin carbohydrate analog carbohydrate biosynthesis ceramides chemical kinetics contraceptives drug design /synthesis /production enzyme inhibitors glycosidases glycosphingolipids nucleoside analog stereochemistry

项目摘要

Cell-surface carbohydrates play key roles in many important biological phenomena, e.g. cell-cell recognition, cell-cell adhesion, cell-matrix adhesion, lymphocyte trafficking, and inflation. Understanding the enzymes which process important glycosidic bonds in complex carbohydrates, glycoproteins, and glycolipids has become a central goal of glycochemistry in basic research and medicine. Drugs based on these targets will also be useful in treating diabetes, metastatic cancer and lysosomal storage diseases; some may display potent antiviral and antitumor properties as well. This renewal proposal outlines four specific objectives for study. (l) The synthesis of nagstatin (and other N-acetyl-D-glucosaminidase inhibitors) can lead to new contraceptives, and limit tumor cell metastasis. Other heterocyclic "glycomimetics" (for example, specific inhibitors of glucosidase II) could be of value in elucidating the role of calnexin (a chaperonin) in protein folding. Several new heterocyclic glycosidase inhibitors have been designed to resemble the conformationally flattened transition state of glucoside hydrolysis. (2) Galactosphingolipids have been implicated in an alternative pathway for HIV-1 infection in CD4-negative cells. By using galactosylceramide analogs to map glycolipid binding to the native HIV coat protein gpl20 and its fragments, prospective new strategies for antiviral therapy will be developed. In related work, inhibitors of glucosylceramide synthase will be synthesized to elucidate the metabolic roles of sphingolipids in cancer malignancy, tumor growth and metastasis. (3) Several new families of ribo- and arabino-nucleoside analogs will be synthesized by replacing the pentose ring with amidrazones, amidoximes and guanidines, leading to unprecedented chemical entities. These entities contain two uncommon structural elements (C=N, arylhydrazino linkage), neither of which is found in database searches of synthetic nucleosides evaluated at NIH for biological activity. However, they are clearly recognized by nucleoside processing enzymes like nucleoside hydrolase, and will be screened against nucleoside kinases, DNA polymerases, and reverse transcriptases. (4) Efforts to synthesize carbocyclic glycosidase inhibitors, like the trehalase inhibitor trehazolin, will focus on a stereoselective new route to pseudopentoses and pseudo-aminopentoses, and on glycoprotein and glycolipid analogs of these novel glycomimetics.

细胞表面碳水化合物在许多重要的生物学过程中发挥着关键作用现象，例如细胞-细胞识别、细胞-细胞粘附、细胞-基质粘附、淋巴细胞运输和膨胀。了解酶它处理复杂碳水化合物中重要的糖苷键，糖蛋白和糖脂已成为糖化学的中心目标在基础研究和医学方面。基于这些靶点的药物也将可用于治疗糖尿病、转移性癌症和溶酶体储存疾病；有些可能表现出有效的抗病毒和抗肿瘤特性，例如出色地。该更新提案概述了四个具体的研究目标。 (l) nagstatin（和其他N-乙酰基-D-氨基葡萄糖苷酶）的合成抑制剂）可以产生新的避孕药，并限制肿瘤细胞转移。其他杂环“糖模拟物”（例如，特定的葡萄糖苷酶 II 的抑制剂）可能有助于阐明蛋白质折叠中的钙联蛋白（伴侣蛋白）。几种新杂环糖苷酶抑制剂的设计类似于构象糖苷水解的平坦过渡态。 (2) 半乳鞘脂与替代途径有关用于 CD4 阴性细胞中的 HIV-1 感染。通过使用半乳糖神经酰胺类似物绘制糖脂与天然 HIV 外壳蛋白 gpl20 结合的图谱，其片段，抗病毒治疗的前瞻性新策略将是发达。在相关工作中，葡萄糖神经酰胺合酶抑制剂将合成以阐明鞘脂在癌症中的代谢作用恶性肿瘤、肿瘤生长和转移。 (3) 几个新的核糖和阿拉伯核苷类似物家族将被通过用氨基腙、偕胺肟等取代戊糖环而合成胍，导致前所未有的化学实体。这些实体包含两个不常见的结构元素（C=N，芳基肼键），在合成核苷的数据库搜索中都没有找到这两种物质 NIH 对其生物活性进行了评估。然而，他们显然被核苷加工酶如核苷水解酶识别，并且将针对核苷激酶、DNA 聚合酶和反向筛选转录酶。 (4) 碳环糖苷酶抑制剂的合成研究海藻糖酶抑制剂trehazolin，将专注于立体选择性新途径假戊糖和假氨基戊糖，以及糖蛋白和这些新型糖模拟物的糖脂类似物。