RECEPTORS AND CARRIERS FOR ANTIVIRAL AGENTS

该项目的目标是解决长期存在的毒品问题 交付. 具体而言，该项目涉及提供 现代抗病毒化疗的佐剂，设计的受体能够 通过各种疏水膜运输核苷酸类似物 隔栏.这样的运输代理商，凭借扩大现有的 可用的抗病毒药物库，可以发挥重要作用， 增强了我们治疗疱疹等衰弱疾病的能力， 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 调节上皮细胞氯阴离子排出的增加， 为分子水平的治疗提供了一种新的重要武器， 囊性纤维化 先前的工作已经导致了特异性核酸碱基的开发 识别单位和一种新的方法，磷酸盐结合的基础上， 质子化膨胀卟啉的用途。 本项目将建设 并提供了用于核苷酸转运的载体系统， 在中性pH和核酸碱基特异性下均有效。 这 将通过制备含有两种受体的双配位受体，如1， 用于磷酸盐结合和嘌呤/嘧啶的扩展的卟啉部分 用于特异性核酸碱基识别的“附加物”。 以下 适当的背景工作，其中的关键机制的特点， 扩展的卟啉-阴离子相互作用（包括氯离子）是 定义，这些和其他有前途的系统将被测试为假定的 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， 在受体结构方面进行分析，并用作 制备尚未改进的识别剂和运输剂。 通过这种方式， 提出了一组临床上可行的抗病毒药物载体， 由于目前NIH赞助的 research. 还提出了类似的设计顺序， 综合、测试和分析可用于开发扩展的 能够实现临床调节的卟啉基载体 细胞氯离子浓度。 在这种情况下， 系统将不需要基于核酸附属物，因此应当 更容易准备和测试。

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.