Our long term goal is to develop nonnucleoside molecules which will be clinically useful against human immunodeficiency virus (HIV). We have found a class of aryl diamidine compounds which have significant anti-HIV activity and which we have shown bind by intercalation to RNA. We propose a number of modifications to increase the RNA binding and eliminate the DNA binding of these compounds. We have discovered naphthalene diimides which preferentially bind to RNA-DNA relative to RNA or DNA. We propose a strategy to develop these compounds into useful anti-AIDs agents. In addition, we propose a new drug design approach which has as its goal to inactivate the virus at the initial stages of replication by specific interaction of newly designed compounds with the HIV-1 gene control regions (TAR and RRE). Molecules which will specifically recognize certain features of HIV RNA are termed RASORS (RNA-specific organic repressors), and are comprised of a RNA duplex recognition unit (RNA intercalator) and a RNA bulge base(s), loop or base pair mismatch recognition unit. Catalytic RASORS (chemical nucleases) contain a third unit which serves as a proton transfer system, with tuneable pka, in order to hydrolytically cleave the RNA. The design of RASORS and catalytic RASORS relies heavily on molecular modeling to predict appropriate geometric relationships between the functional units and the target RNA. Close collaboration with the Biological Core and the Biophysical Group (Project 4) will provide rapid feedback on the effect of structure modifications on anti-HIV activity and nucleic acid binding. The coupling of this data along with molecular modeling should provide insights which will allow rapid recognition of the optimum molecules in each system.
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