Studies of Antitumor,Anti HIV Cyclic Depsipeptides

环缩酚肽抗肿瘤、抗HIV的研究

• 批准号: 6619475
• 负责人: MARK A LIPTON
• 金额: $ 30万
• 依托单位: PURDUE UNIVERSITY
• 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 2005-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6619475
• 关键词: affinity labeling; animal extract; antiAIDS agent; antineoplastics; chemical models; cyclic peptides; cytoprotection; cytotoxicity; drug discovery /isolation; drug receptors; monoclonal antibody; nuclear magnetic resonance spectroscopy; peptide analog; protein structure function; structural biology

DESCRIPTION: (provided by applicant) Three families of cyclic depsipeptides, all recently isolated from different shallow water sponges in the Pacific, display cytotoxicity against a broad spectrum of tumor cell lines (mean 1C50= 75 ng/mL), most notably including multidrug-resistant cell lines. All three families also protect T-cells against infection by HIV-1 (EC50= 3.6 ng/mL). Additionally, preliminary studies in our laboratory have indicated that at least one of these molecules may induce apoptosis in tumor cells. The origins of these effects are unknown at present. These families share many common structural features, including a number of novel, non-proteinogenic amino acids, but have not been fully structurally characterized. The first goal of this proposal is to complete the structural elucidation of these natural products through solid phase synthesis, correlation studies, NMR spectroscopy and molecular modeling. The second goal of this project is to investigate the cellular modes of action of these molecules through the synthesis and use of fluorescently labeled derivatives and affinity labeling probes. The fluorescent probes will be used to study cellular localization and investigate whether such molecules can cross plasma membranes. The affinity probes will be used to label high affinity binding sites for these molecules and to identify potential receptor proteins. A third goal of this project is to dissect the roles played by many of the novel residues in these molecules. This will be accomplished by mutating selected residues and examining the effects on structure, cytotoxicity and/or interaction with a cellular receptor. The combination of structural studies and cytotoxicity assays will be used to create a pharmacophore model that accounts for the similar activities of all three families. Development of a pharmacophore model will permit the design of non-peptidic analogues that mimic the activities of the natural products. The final goal of this project will be to fmd an endogenous protein ligand to the receptor for the cyclic depsipeptides. Monoclonal antibodies raised against a cyclic depsipeptide hapten will be used to search for such a protein ligand.

描述：（由申请人提供）三个环状缩酚肽家族，最近均从太平洋的不同浅水海绵中分离出来， 对多种肿瘤细胞系表现出细胞毒性（平均值 1C50= 75 ng/mL），最值得注意的是包括多重耐药细胞系。全部三个 家庭还可以保护 T 细胞免受 HIV-1 感染（EC50= 3.6 ng/mL）。 此外，我们实验室的初步研究表明，在 这些分子中至少有一种可以诱导肿瘤细胞凋亡。起源 目前尚不清楚这些影响的具体情况。这些家族具有许多共同的结构特征，包括许多新颖的非蛋白氨基酸 酸，但尚未完全进行结构表征。第一个目标是 该提案旨在完成这些自然物质的结构阐明 通过固相合成、相关研究、核磁共振波谱获得的产品 和分子建模。该项目的第二个目标是调查 这些分子通过合成和使用的细胞作用模式 荧光标记衍生物和亲和标记探针。荧光的 探针将用于研究细胞定位并调查是否存在这种情况 分子可以穿过质膜。亲和探针将用于标记 这些分子的高亲和力结合位点并识别潜在的 受体蛋白。该项目的第三个目标是剖析所扮演的角色 由这些分子中的许多新残基决定。这将通过以下方式完成 突变选定的残基并检查对结构、细胞毒性的影响 和/或与细胞受体的相互作用。结构组合 研究和细胞毒性测定将用于创建药效团模型 这就是三个家庭的类似活动的原因。发展 药效团模型将允许设计非肽类似物 模仿天然产物的活性。该项目的最终目标 将找到环状受体的内源蛋白配体 缩酚肽。针对环缩酚肽产生的单克隆抗体 半抗原将被用来寻找这样的蛋白质配体。