Nucleotide-Guanidinoglycoside Conjugates as Anti-HIV Agents

Yitzhak Tor, UC-San Diego
Biomedical and Clinical Sciences

The rapid appearance of resistant HIV-variants, adverse effects on contemporary drugs, recent indications for HIV "superinfections" and disappointing results with experimental vaccines, all necessitate the continuous development of independent therapeutic strategies to combat HIV infection. The goals of the proposed project are to design, synthesize and evaluate novel nucleotideguanidinoglycoside conjugates as potential anti HIV-1 agents.

The underlying hypothesis guiding the proposed strategy is that the anti HIV efficacy of nucleoside-based ReverseTranscriptase inhibitors (NRTIs) can be enhanced by covalently conjugating their corresponding monophosphates to guanidinoglycosides, a novel family of cellular uptake vehicles that also exhibit high affinity to viral RNA sequences. Two objectives are therefore concomitantly met: (1.) RT inhibitors are actively transported into the cell and then released in a semi-activated form, hence the necessary monophosphorylation step is circumvented, and (2.) essential regulatory events involving viral-specific protein-RNA interactions (e. g., Rev-RRE) are inhibited.

The unique fundamental as well as practical features offered by this approach include: (1.) two distinct stages in the lifecycle of the virus are targeted with one anti-HIV agent, and (2.) facilitated import of semi-activated NRTI's may enhance the therapeutic factor of clinically proven agents (since fewer metabolic activation steps are needed and the released negatively charged nucleotide may reside longer in the cell), and possibly revive NRTI's that have clinically never materialized due to lack of appropriate metabolic activation.