ANTIHIV OLIGONUCLEOTIDES WITH REACTIVE FUNCTIONAL GROUPS

Johns Hopkins University, Baltimore MD

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Abstract

DESCRIPTION: Antisense and triplex-forming oligonucleotides are research tools that can be used to characterize gene expression in cell culture and may have potential therapeutic applications in the treatment of AIDS and AIDS-related diseases. This project will focus on strategies to enhance the affinities of nuclease-resistant oligo-2'-O-methylribonucleotide analogs that contain alternating methyiphosphonate-phosphodiester internucleotide bonds, mr-AOMP (2'-O-rnethylnbo-alternating Qligonucleoside methylQhosphonates) for their RNA or DNA targets with the expectation that such enhanced affinity will translate into enhanced biological activity. Antisense mr-AOMPs targeted to HIVI TAR RNA or to RRE RNA will be synthesized that contain: (1) affinity enhancing bases such as 5-propynyl-U, 5-propynyl-C or a G-clamp heterocycle; (2) site-specific, chiral methylphosphonate linkages; (3) an affinity enhancing aminooxyquinoline (AOQ) group; or (4) novel imidazole RNA cleaving groups. The interactions of these mr-AOMPs with TAR or RRE RNA will be characterized. Triplex-forming mr-AOMPs targeted to polypurine tracts in the env or gag genes of HIV-1 proviral DNA will be synthesized that contain: (1) base analogs such as 5-propynyl-U, pseudoiso-C or 8-oxo-A; (2) methylphosphonate linkages of defined configuration; or (3) an affinity enhancing AOQ group. Their interactions with synthetic env- or gag-DNA targets will be investigated. The effects of antisense mrAOMPs on Tat protein-TAR or Rev protein-RRE interactions in v/tm will be studied in collaboration with Dr. Tariq Rana, Robert Wood Johnson School of Medicine. Strategies to enhance the uptake of mrAOMPs in cell culture will be explored and the anti-viral activities of selected oligomers will be investigated in collaboration with Dr. Jeffrey Laurence, Cornell Medical Center.