Senseless nucleic acid macromolecules: synthesis, charatcerization and biological studies

A substantial amount of research is currently being undertaken to create new anti-Human Immunodeficiency Virus (HIV) drugs. Currently, 14 drugs belonging to three classes are approved for use in the treatment of HIV. Combination therapy utilizing drugs with different mechanisms of action does initially suppress HIV proliferation, however, after time, selection for mutationally altered particles leads to the development of Acquired Immune Deficiency Syndrome (AIDS). To combat this disease, additional drugs must be developed that have either unique targets or alternative mechanism of actions in order to avoid cross-resistance with the established drugs. Previous work in this lab has defined a new class of HIV inhibitors. Various thiolated amphipathic polyribonucleotides that are "senseless" and have no hydrogen bonding potential, are shown to have submicromolar activity against HIV and additionally against HCMV. Though the mechanism of HCMV inhibition is not known it has been theorized that in a HIV infected cell, the macromolecules are acting as antitemplates and interfering with the transcriptional process of reverse transcriptase (RT). Pursuit of analogs has identified a new subclass of highly active homopolymers that deviate from the previously established SAR. Among the most active compounds are poly (1-propargylinosinic acid), 2'-O-methyl-1-allylinosinic acid phosphorothioate 33-mer and a oligomer incorporating 1-propargyl-6-thioinosinic acid residues. Structure activity relationship (SAR) studies within this new group of compounds show that various aspects of sulfur incorporation, polymer length, steric bulk at N1 and the formation of secondary structure in solution are important for activity but that amphipathic character is necessary. Cell uptake studies with a fluorescently labeled oligomer support the working hypothesis that these compounds could inhibit RT in the cytoplasm. Additionally, the data show that the process involving viral uptake could also be blocked by these macromolecules. Described herein is the synthesis and complete characterization of two different groups of antitemplate compounds, their respective biological activities and preliminary studies describing cell surface binding and intracellular penetration.