This proposal discusses the development of small molecule, orally active antiviral agents designed to halt replication of the AIDS virus at the level of transcription by inhibiting the Rev protein/RRE interaction. This protein/nucleic acid interaction is essential for viral replication.(1-3) Zapp and coworkers demonstrated for the first time that a small molecule aminoglycoside antibiotic, neomycin B, could disrupt the Rev/RRE interaction.(4) The aminoglycoside antibiotics however possess cytotoxicity, bioavailability, and binding site selectivity profiles that require improvement.(5-9) In an effort to solve these problems, we would like to step away from the aminoglycoside antibiotic skeleton, and yet have our compounds retain spatial similarity to the parent molecule. We propose to use as our central building block 2-deoxystreptamine, the same aminocyclitol that is found in virtually all of the naturally occurring aminoglycoside antibiotics. Derivatization of 2-deoxystreptamine (2-DOS) with non-carbohydrate moieties, whose functional groups are in accord with our proprietary structure activity data, will very rapidly afford neomycin B mimics that display the desired inhibitory properties while having improved therapeutic indices. Determination of compound efficacy is performed in house using cell-based and multiple in vitro assays.
An estimated one million people in the United States and 17 million world wide are infected with the AIDS virus.(11) In the U. S. 243,000 people have already died of AIDS. Very few drugs have been approved for this disease and the drugs that are available have severe limitations.(12) Furthermore, the virus is mutating and the development of resistance to the existing therapeutics is rapidly becoming a serious problem.(12) To help overcome this resistance it is probable that new therapeutic approaches will require combination therapy. Inhibition of the Rev/RRE interaction with small orally active molecules will be very appropriate for such combinations because their mode of action and locus of activity are quite distinct from reverse transcriptase and protease inhibitors.
