POLYPYRROLE BASED ANION RECEPTORS

基于聚吡咯的阴离子受体

• 批准号: 6184001
• 负责人: Jonathan L Sessler
• 金额: $ 26.64万
• 依托单位: UNIVERSITY OF TEXAS AT AUSTIN
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-01-01 至 2003-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6184001
• 关键词: anions; chemical binding; chloride ion; cystic fibrosis; drug design /synthesis /production; drug receptors; drug screening /evaluation; epithelium; fluorescent dye /probe; ion transport; metabolism disorder chemotherapy; phosphates; porphyrins; pyrroles; reagent /indicator

The goal of this project is to solve a long-standing problem in drug delivery. Specifically, this project is concerned with providing adjuvants for modern antiviral chemotherapy, designed receptors capable of transporting nucleotide analogues through various hydrophobic membrane barriers. Such transport agents, by virtue of expanding the available arsenal of useable antiviral agents, could play an important role in augmenting our ability to treat such debilitating diseases as herpes, hepatitis, measles, and AIDS. Related to the above, and ancillary as a project objective, is the preparation of selective receptors and carriers for chloride anion. These, by possibly allowing for a clinically regulated increase in epithelial cell chloride anion egress, could provide a new and important weapon for the molecular level treatment of cystic fibrosis. Prior work has led to the development of both specific nucleic acid base recognition units and a new approach to phosphate binding based on the use of protonated expanded porphyrins. The present project will build on this work and provide carrier systems for nucleotide transport that are both effective at neutral pH and nucleic acid base specific. This will be done by preparing ditopic receptors, such as 1, that contain both expanded porphyrin moieties for phosphate binding and purine/pyrimidine "appendages" for specific nucleic acid base recognition. Following appropriate background work, in which the key mechanistic features of expanded porphyrin-to-anion interactions (including chloride) are defined, these and other promising systems will be tested as putative nucleotide analogue transport agents. This will be done first using model membrane systems and then using virus-infected cell lines. From the results of these studies and those of standard acute toxicity tests, adjuvant efficacy will be assessed. This efficacy will then, in turn, be analyzed in terms of receptor structure and used as the basis for preparing yet-improved recognition and transport agents. In this way, it is proposed, a clinically viable set of carriers for antiviral drug delivery can be produced as the result of the present NIH-sponsored research. It is also proposed that a similar sequence of design, synthesis, testing, and analysis can be used to develop expanded porphyrin based carriers capable of effecting clinical regulation of cellular chloride anion concentration. In this case, the requisite system will not require a nucleic acid base appendage and should hence be much easier to prepare and test.

该项目的目标是解决药物领域长期存在的问题 送货。 具体来说，该项目涉及提供 现代抗病毒化疗的佐剂，设计的受体能够 通过各种疏水膜转运核苷酸类似物 障碍。此类运输代理凭借扩大可用的 可用的抗病毒药物库可以发挥重要作用 增强我们治疗疱疹等使人衰弱的疾病的能力， 肝炎、麻疹和艾滋病。 与上述相关，并作为辅助 项目目标，是制备选择性受体和载体 对于氯阴离子。 这些，通过可能允许临床 上皮细胞氯阴离子排出量的调节增加，可以 为分子水平治疗提供新的重要武器 囊性纤维化。 先前的工作导致了特定核酸碱基的开发 识别单元和基于磷酸盐结合的新方法 质子化扩张卟啉的使用。 本项目将建设 开展这项工作并提供用于核苷酸运输的载体系统 在中性 pH 值和核酸碱基特异性下均有效。 这 将通过制备双位受体来完成，例如 1，其中包含 用于磷酸盐结合和嘌呤/嘧啶的扩展卟啉部分 用于特定核酸碱基识别的“附件”。 下列的 适当的背景工作，其中的关键机制特征 扩大的卟啉与阴离子相互作用（包括氯）是 定义，这些和其他有前途的系统将作为假定的进行测试 核苷酸类似物转运剂。 这将首先使用 模型膜系统，然后使用病毒感染的细胞系。 从 这些研究的结果和标准急性毒性试验的结果， 将评估辅助功效。 这种功效将反过来， 根据受体结构进行分析并用作 准备尚未改进的识别和传输代理。 这样， 提出了一组临床上可行的抗病毒药物载体 交付可以通过目前 NIH 资助的结果来实现 研究。 还建议采用类似的设计顺序， 合成、测试和分析可用于开发扩展 基于卟啉的载体能够影响临床调节 细胞氯阴离子浓度。 在这种情况下，需要 系统不需要核酸碱基附件，因此应该 更容易准备和测试。