NEW INTERACTIONS OF ANTIMITOTIC AGENTS

抗有丝分裂剂的新相互作用

• 批准号: 2895246
• 负责人: MARC L SNAPPER
• 金额: $ 10.27万
• 依托单位: BOSTON COLLEGE
• 依托单位国家: 美国
• 财政年份: 1995
• 资助国家: 美国
• 起止时间: 1995-06-01 至 2000-06-01
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2895246
• 关键词: analog; antimitotics; chemical structure function; combinatorial chemistry; drug interactions; intermolecular interaction; intracellular transport; microtubules; paclitaxel; quinones; receptor binding; sesquiterpenes; tubulin; vesicle /vacuole

Important human health concerns, including: cancer, bacterial and viral infection, atherosclerosis, and neurodegenerative diseases, all to various degrees, involve components of the endosomal network. The functions of the endosomal network are, in part, dependent on microtubules. Our insufficient understanding of the endosomal and microtubule network has been obtained, partially, through the study of their interactions with small molecules. Considering the value of small molecules as probes of biological function, this research project outlines the use of new probes derived from biologically active, and medicinally important, natural products. Our immediate goal is t further elucidate the mechanism of action of several biologically active small molecules that interact with microtubules, endosomal, and other protein receptors. These mechanistic clarifications will include the identification and characterization of new small molecule receptors, as well as more detailed studies of known small molecule/receptor interactions. Details of these interactions should provide new targets for selective chemotherapeutic interventions. For example, ilimaquinone ('lima-quinone'), an antimitotic, anti-HIV, sesquiterpenoid quinone, is reported to have profound effects on endosomal trafficking. The biologically relevant target of this natural product will be pursued using active analogs of ilimaquinone. In a related manner, avarone, a structurally similar natural product, also with significant antimitotic activity, will be modified such that its receptor can be identified and characterized. Agents that inhibit specific endosomal events could be used to control intracellular trafficking of cholesterol or beta-amyloid; or possibly inhibit viral entry into the cell. In addition, to better explain the mechanism of action of important antimitotic agents a search for small molecule mediated interactions with microtubules will be initiated. Novel binding assays will examine both the inhibition of, and the promotion of, new protein-microtubule interactions in the presence of several antimitotic agents, including ilimaquinone, avarone, and the anticancer drug taxol. Protein co- receptors found for these antimitotic agents will be identified and characterized. Furthermore, to study known and unknown interactions, a combinatorial search of small molecule binding to tubulin will be undertaken. Identification and study of interactions of the endosomal and microtubule network will provide new opportunities for designing agents with highly specific interactions. Inhibition of specific microtubule or endosomal activities with these agents could represent new strategies for controlling a number of diseases.

重要的人类健康问题，包括：癌症、细菌和病毒 感染、动脉粥样硬化和神经退行性疾病，所有这些都与各种 度，涉及内体网络的组成部分。的功能 内小体网络部分地依赖于微管。我们的 对内体和微管网络的了解不足 部分是通过研究它们与人的相互作用而获得的 小分子。 考虑到小分子作为生物功能探针的价值， 这项研究项目概述了从 具有生物活性和重要药用价值的天然产品。我们的 眼下的目标是进一步阐明几种 与微管相互作用的生物活性小分子， 内体和其他蛋白质受体。这些机械的澄清 将包括新小分子的鉴定和表征 受体，以及对已知的小分子 分子/受体相互作用。这些交互的详细信息应该 为选择性化疗干预提供新的靶点。 例如，利马喹酮，一种抗有丝分裂，抗艾滋病毒， 倍半萜类化合物，据报道对内涵体有深远的影响 贩卖人口。这种天然产物的生物相关靶标 将使用活性的伊利马喹酮类似物进行研究。在相关的 一种结构相似的天然产品，也有 显著的抗有丝分裂活性，将被修饰以使其受体 可以被识别和表征。抑制特定基因的药物 内体事件可以用来控制细胞内的转运 胆固醇或β-淀粉样蛋白；或可能抑制病毒进入 手机。 此外，为了更好地解释重要的作用机制 抗有丝分裂药物寻找小分子介导的相互作用 微管将被启动。新的结合分析将检查这两种方法 抑制和促进新的蛋白质-微管 在几种抗有丝分裂药物存在下的相互作用，包括 伊利马喹酮、阿瓦隆和抗癌药物紫杉醇。蛋白质共- 为这些抗有丝分裂药物发现的受体将被识别并 特色化的。此外，为了研究已知和未知的相互作用，一个 与微管蛋白结合的小分子的组合搜索 承担了。 内小体与微管相互作用的鉴定与研究 网络将为设计高度高效的代理提供新的机会 特定的交互作用。抑制特定的微管或内小体 与这些代理的活动可能代表着 控制一些疾病。