Antisense oligonucleotides are research tools used to study gene expression in cell culture and have potential therapeutic applications in the treatment of AIDS and AIDS-related diseases. The efficacy of antisense oligomers can in theory be increased by specific modifications of the oligonucleotide backbone which enhance hybridization with the target and by derivatization of the oligonucleotide with functional groups which enable the oligomer to interact covalently with its target. To test this hypothesis, the Principal Investigator proposes to synthesize novel, nuclease-resistant, oligonucleotides which have alternating methylphosphonate-phosphodiester backbones. Oligomers composed of 2'-O-methylribonucleosides will be designed to form duplexes with complementary sites in HIV mRNA. Oligomers composed of 2'-deoxyribonucleosides will be designed to form triplexes with purine tracts in HIV proviral DNA. These oligomers will be further derivatized with an epoxide functional group to enable alkylation of a G residue in the target or by an aminooxyethyl group to enable Michael adduct formation with a C residue in the target. The interactions of these oligonucleotides with synthetic RNA and DNA targets will be examined. Collaborative studies will be carried out to determine if the oligonucleotides bearing the reactive functional groups have enhanced anti-HIV activity in cell culture compared to non-reactive controls.
| Saleh, Anthony D; Miller, Paul S (2011) Hydrolysis of bulged nucleotides in hybrids formed by RNA and imidazole-derivatized oligo-2'-O-methylribonucleotides. Nucleosides Nucleotides Nucleic Acids 30:235-55 |
| Campbell, Meghan A; Miller, Paul S (2009) Cross-linking to an interrupted polypurine sequence with a platinum-modified triplex-forming oligonucleotide. J Biol Inorg Chem 14:873-81 |
| Campbell, Meghan A; Miller, Paul S (2009) Transplatin-conjugated triplex-forming oligonucleotides form adducts with both strands of DNA. Bioconjug Chem 20:2222-30 |
| Campbell, Meghan A; Miller, Paul S (2008) Phosphodiester-mediated reaction of cisplatin with guanine in oligodeoxyribonucleotides. Biochemistry 47:12931-8 |
| Prater, Chrissy E; Saleh, Anthony D; Wear, Maggie P et al. (2007) Chimeric RNase H-competent oligonucleotides directed to the HIV-1 Rev response element. Bioorg Med Chem 15:5386-95 |
