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.
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