The long range goal of this project is to prepare and characterize expanded porphyrin-based receptors that function as carriers for the into-cell transport of pharmacologically important nucleotide analogs, antisense oligodeoxynucleotides, and DNA fragments. Such transport agents could dramatically improve treatment of viral diseases as well as make clinically viable the emerging fields of antisense technology and gene therapy. To date, significant progress has been made. for instance, model U-tube experiments carried out using a first set of expanded porphyrin based carriers demonstrated that this basic approach will work in effecting the efficient transport of targeted nucleotide monophosphates at neutral pH. With this application the applicants now request funds so as to be able to extend this work. Specifically, they propose to prepare improved carriers for nucleotides, look also at oligonucleotide transport, and carry out cellular studies. They will pursue this proposed work in the following stages: 1. Prepare and study polytopic sapphyrin receptors specifically designed to facilitate into- cell transport of 3'-azido-3'-deoxythymidine monophosphate and triphosphate (AZT - MP and TP) and/or 9-(2-hydroxyethoxymethyl) guanine monophosphate (acyclovir-MP). 2. Prepare and generate cholesterol- substituted expanded porphyrins and study these as membrane channels for nucleotide transport. 3. Synthesize expanded porphyrin-bearing natural polymers specifically modified so as to effect the trans-membrane transport of antisense oligonucleotides and DNA fragments.
