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中起关键作用现象，例如细胞细胞识别，细胞 - 细胞粘附，细胞 - 矩阵粘附，淋巴细胞运输和通货膨胀。了解酶哪种过程中重要的糖苷键在复杂的碳水化合物中，糖蛋白和糖脂已成为糖化学的核心目标基础研究和医学。基于这些目标的药物也将是用于治疗糖尿病，转移性癌和溶酶体储存疾病；有些可能显示出有效的抗病毒和抗肿瘤特性出色地。该更新建议概述了四个特定的研究目标。（l）Nagstatin（和其他N-乙酰-D-葡萄糖胺酶的合成）抑制剂）可以导致新的避孕药，并限制肿瘤细胞转移。其他杂环“ GlyComimimitics”（例如，特定葡萄糖酶的抑制剂II）在阐明的作用中可能具有价值蛋白质折叠中的钙粘蛋白（伴侣蛋白）。几个新的杂环糖苷酶抑制剂已设计为类似于构象葡萄糖苷水解的扁平过渡态。（2）银磷脂已与替代途径有关用于CD4阴性细胞中的HIV-1感染。通过使用半乳糖酰胺类似于映射与天然HIV HIV外套蛋白GPL20和它的碎片，前瞻性的抗病毒治疗策略将是发达。在相关工作中，葡萄糖基酶合酶的抑制剂将合成以阐明鞘脂在癌中的代谢作用恶性，肿瘤生长和转移。（3）核糖和阿拉伯核苷类似物的几个新家庭将是通过用amidrazones，amidoximes和圭尼酮，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hydrazino链接），在合成核苷的数据库搜索中都没有找到它们在NIH评估生物学活性。但是，他们显然是通过核苷加工酶（如核苷水解酶）识别，和将针对核苷激酶，DNA聚合酶和反向筛选转录酶。（4）努力合成碳环糖糖苷酶抑制剂，例如 Trehalase抑制剂Trehazolin，将重点放在立体选择性的新路线上伪肠疾病和伪氨基肠疾病，以及糖蛋白和糖蛋白这些新型糖纤维的糖脂类似物。