Studies of Antitumor,Anti HIV Cyclic Depsipeptides

环缩酚肽抗肿瘤、抗HIV的研究

• 批准号: 6422725
• 负责人: MARK A LIPTON
• 金额: $ 25.65万
• 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 2005-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6422725
• 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）三个家族的环状缩酚肽， 这些都是最近从太平洋不同的浅水海绵中分离出来的， 显示对广谱肿瘤细胞系的细胞毒性（平均1C 50 = 75 ng/mL），最值得注意的是包括多药耐药细胞系。所有三 家族还保护T细胞免受HIV-1感染（EC 50 = 3.6 ng/mL）。 此外，我们实验室的初步研究表明， 这些分子中的至少一种可以诱导肿瘤细胞的凋亡。起源 这些影响目前尚不清楚。这些家庭有许多共同点， 结构特征，包括一些新的，非蛋白质氨基 酸，但尚未完全结构化。的第一个目标 该建议是为了完成这些天然产物的结构解析， 产品通过固相合成，相关性研究，NMR光谱 和分子建模。该项目的第二个目标是调查 这些分子的细胞作用模式通过合成和使用 荧光标记的衍生物和亲和标记探针。荧光 探针将被用于研究细胞定位，并调查是否这样的 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，并鉴定潜在的 受体蛋白本项目的第三个目标是剖析 这些分子中的许多新残基。这将通过 突变选定的残基并检查对结构、细胞毒性 和/或与细胞受体的相互作用。结构的组合 研究和细胞毒性试验将用于创建药效团模型 这就解释了这三个家庭的相似活动。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。这个项目的最终目标 将是找到一个内源性蛋白质配体的受体， 缩肽抗环缩肽的单克隆抗体 半抗原将用于寻找这样的蛋白质配体。