Antisense phosphodiester oligonucleotides, conjugated with acridine, and antisense methylphosphonate oligonucleotides, killed cultured Trypanosome brucei in the Phase I program. In the Phase II program, antisense olignucleotides will be edified at the base, sugar, and phosphodiester functional groups to increase their therapeutic potency. These modifications will be designed to increase oligonucleotide cell penetration, stability, and functional inhibition of target RNA or DNA. The nucleic acid target will be expanded beyond the 39 nucleotide spliced leader sequence of trypanosome mRNAs to include the small nuclear RNAs, the coding and non-coding of several mRNA sequences, and the actin gene promoter region. Modified oligonucleotides then will be tested against the trypanosome procyclic form in culture, and those with enhanced therapeutic activity against the bloodstream form. Active oligonucleotides will be tested for therapeutic efficacy using trypanosome infected mice. Positive results will be of interest to the pharmaceutical industry for the development of new antisense oligonucleotide chemotherapeutic agents for trypanosomes and other parasites.
| Reed, M W; Adams, A D; Nelson, J S et al. (1991) Acridine- and cholesterol-derivatized solid supports for improved synthesis of 3'-modified oligonucleotides. Bioconjug Chem 2:217-25 |
