With recent unsettling events foreshadowing an increased sense of urgency, NIAID has targeted research and development of therapeutics, vaccines, adjuvants/immunostimulants, and diagnostics for small pox and other viral diseases. At TSRL, Inc., we have been developing a prodrug strategy for the improvement of antiviral drugs. Strategies that can improve the oral bioavailability of approved drugs as well as potential drug candidates will facilitate the development of highly effective antiviral agents and reduce undesirable properties such as drug toxicity, poor patient compliance, and high costs associated with current therapy. The long-term goal of this project is to improve the oral absorption of poorly absorbed drugs and to enhance their delivery to specific tissues, thus improving efficacy. The central hypothesis of this application is that oral absorption of poorly absorbed drugs can be improved and drugs can be specifically targeted to the cells of interest by designing prodrugs targeted to transporters expressed in human intestine and targeted to """"""""activation"""""""" enzymes that specifically cleave the prodrug moiety to its parent compound. For this project, we propose to synthesize a variety of peptide prodrugs of the cidofovir and floxuridine and test them for transporter-mediated uptake and cellular and plasma hydrolysis. Our goal is to identify prodrug candidates that show enhanced carrier-mediated uptake and/or viral-specific activation. Those candidate drugs showing enhanced uptake or activation will be tested for antiviral activity against vaccinia and cowpox viruses as well as for cytotoxicity in two human cell lines. Further, candidate drugs showing enhanced uptake or activation and antiviral activity will be tested for oral bioavailability in test animals. The expected outcome of this Phase 1 SBIR project is the development of amino acid prodrug analogs of the test drugs that show enhanced bioavailability and/or targeted activation and therefore have potential as superior oral therapeutic agents for treatment of pox virus disease. Further, completion of the project will position TSRL for future prodrug development for treatment of a wide variety of disease states.
