Viral proliferation and most cellular functions require the interaction of regulatory proteins with their cognate recognition sequences. We wish to identify small molecules that will interfere with these DNA:protein interactions by binding in a sequence-specific manner to the DNA recognition site. DNA-binding molecules may have extremely broad applications as antiviral, anticancer, or antimicrobial drugs. Immunosuppression and cardiovascular diseases are other potential targets for DNA-binding molecules. We have developed a high-throughput screening assay for detecting DNA-binding molecules. The assay is designed to determine the relative affinity of these molecules for virtually any short DNA sequence and can be used to screen large libraries of crude biological mixtures or synthetic chemicals for the presence of novel sequence-specific DNA-binding molecules. In addition, the assay is capable of determining the sequence-specificity of known DNA-binding drugs. In Phase II, we propose to screen known DNA-binding molecules to determine the highest affinity binding sites for each molecule among 256 4-base pair binding sites. These data will be used to design congeners directed to specific critical DNA target sites in viral genomes and medically significant target sites in the human genome.
