Design of anti-HIV compounds: from nucleoside to nucleoside 5'-triphosphate analogs. Problems and perspectives

To date, human immunodeficiency virus infection remains incurable although a variety of antiviral agents have been identified and characterized. Even though nucleoside analogs have been the most successful prodrugs, there remains the need to develop new compounds that exhibit a more favorable toxicity profile, less susceptible to cross-resistance, and greater efficacy. As prodrugs, the nucleoside analogs should be sequentially phosphorylated by cellular kinases to yield triphosphate form before they can inhibit HIV replication at the reverse transcriptase level. The efficiency of phosphorylation of nucleoside analogs is a key factor in their antiviral activity and strongly depends on nucleoside structure and cell type. In recent years, several attempts have been made to improve therapeutic potential of nucleoside analogs by the use of nucleotide prodrugs (pronucleotides), that can avoid the first step of phosphorylation. This review focuses on problems of intracellular phosphorylation of nucleoside analogs and perspectives of developing of a new class of nucleotide analogs modified at phosphate group as a form for the delivery of nucleotide analogs into the cell.