2',3'-Dideoxynucleoside analogs are commonly used as anti-HIV, anti-HBV, and anti-cancer drugs. Despite of their potent activities, there are some major limitations in using 2',3'-dideoxynucleosides as therapeutic agents. The nucleosides have usually poor cellular uptake because of their hydrophilic nature. Some of the nucleoside analogs, such as anti-HIV agents, become ineffective after multiple administrations because of the development of the drug resistance, and therefore they must be administered in combination therapy. It is hard to deliver the nucleoside analogs to a particular tissue for site specific targeting. Furthermore, nucleoside analogs undergo three intracellular phosphorylation steps to become active. The first phosphorylation step is slow and a rate-limiting process for several compounds.
Herein, we report the synthesis and evaluation of 2',3'-dideoxynucleoside conjugates with fatty acids, peptides, other nucleosides, fatty acyl phosphotriesters, or polymer derivatives. The primary hypothesis of this project was that conjugation of nucleosides with other compounds offers a novel strategy in designing compounds with enhanced anti-HIV activity. This combination may result in development of anti-HIV agents having enhanced lipophilicity, longer duration of action by sustained intracellular release of active substrates at adequate concentrations, higher uptake into infected cells, and/or site specificity. The development of viral resistance to the nucleosides would occur at a slower rate than to either compound alone. Furthermore, some of the compounds may be used to bypass first rate-limiting phosphorylation step.
Overall, the research described in this dissertation demonstrated that conjugation of anti-HIV nucleoside analogs with appropriate compounds (e.g., fatty acids, polymers, peptides groups, or other nucleosides) is an alternative strategy for designing more effective anti-HIV agents that can be further developed as therapeutic or preventative agents.
