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 程度，涉及内体网络的组成部分。 的功能 内体网络部分依赖于微管。 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 小分子。 考虑到小分子作为生物功能探针的价值， 该研究项目概述了新探针的使用 具有生物活性且具有重要药用价值的天然产物。 我们的 近期目标是进一步阐明几种药物的作用机制 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。 这些机制的澄清 将包括新小分子的鉴定和表征 受体，以及对已知小分子的更详细研究 分子/受体相互作用。 这些交互的细节应该 为选择性化疗干预提供新的目标。 例如，ilimaquinone（'lima-quinone'），一种抗有丝分裂、抗 HIV、 据报道，倍半萜醌对内体具有深远的影响 贩运。 该天然产物的生物学相关目标 将使用伊利马醌的活性类似物进行研究。 在相关的 方式，阿瓦龙，一种结构相似的天然产物，也具有 显着的抗有丝分裂活性，将被修饰，使其受体 可以被识别和表征。 特定抑制剂 内体事件可用于控制细胞内转运 胆固醇或β-淀粉样蛋白；或可能抑制病毒进入 细胞。 此外，为了更好地解释重要的作用机制 抗有丝分裂剂寻找小分子介导的相互作用 微管将被启动。 新颖的结合测定将检查两者 抑制和促进新蛋白质微管 几种抗有丝分裂剂存在下的相互作用，包括 伊利马醌、阿瓦龙和抗癌药物紫杉醇。 蛋白质辅料 这些抗有丝分裂剂的受体将被鉴定并 特点。 此外，为了研究已知和未知的相互作用， 结合微管蛋白的小分子的组合搜索 进行。 内体和微管相互作用的鉴定和研究 网络将为设计具有高度特征的代理提供新的机会 具体的相互作用。 特定微管或内体的抑制 与这些药物的活动可以代表新的策略 控制多种疾病。