CARB 30 |
| Nucleic acids can have richly diverse structures, including hairpins, knots, pseudoknots, triple helices, loops, helical junctions, and bulges. Such bulged structures in nucleic acids are of general biological significance, proposed as intermediates in a multitude of processes including RNA splicing, frame-shift mutagenesis, intercalator induced mutagenesis, imperfect homologous recombination, as the binding site for the coat protein of bacteriophage, and in the ribosomal synthesizing machinery. Bulges have also been suggested as binding motifs for regulatory proteins involved with viral replication, including the TAR region of HIV-1. Additionally, the etiology of at least 12 human neurodegenerative genetic diseases has been attributed to genetic variations in the lengths of triplet repeats in genomic DNA (e.g. myotonic dystrophy, Huntington's disease, Friederich's ataxia, and fragile X syndrome). The unstable expansion of triplet repeats has been attributed to reiterative synthesis due to slippage and bulge formation in the newly formed DNA strand. As such, compounds capable of binding to bulges could have significant therapeutic potential. The most promising bulge-specific agent discovered to date originated from work on the enediyne natural product NCS-chrom. In the absence of thiols, NCS-chrom undergoes a general base catalyzed intramolecular cyclization to generate a spirocyclic species that specifically cleaves bulged structures (2-3 unpaired bases) in DNA and RNA. Based on this finding, in collaboration with the Goldberg group at Harvard Medical School we have designed libraries of compounds based on the neutral arene product from base catalyzed NCS-chrom degradation (NCSi-gb), and have achieved nM affinity for specific bulged sequences. This presentation will focus on recent findings, including the selective alkylation of bulged sites, library design criteria, and the development of molecular biology probes which induce the slippage process.
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Nucleic Acids as Drug Targets
1:40 PM-4:50 PM, Monday, August 20, 2007 BCEC -- 208, Oral
Division of Carbohydrate Chemistry |