Small molecules that can be programmed to target specific genes would be useful as molecular probes and possibly a new a class of therapeutic agent. Pyrrole-imidazole polyamides are one such class of molecules that can be designed to bind to specific DNA sequences. Polyamides can elicit potent biological responses, such as the inhibition of tumor growth in mice, but the rational use of polyamides remains a challenge. Our group has previously examined the DNA sequence specificity of polyamides across the entire sequence space (Carlson et al, PNAS 2010). But despite several reports that have applied polyamides to studies in fruit flies, mice and human cells, the genome-wide binding preferences of polyamides are unknown. We use bioinformatics to predict binding sites in the context of the genome. We then explore the link between predicted polyamide binding sites and changes in gene expression (Figure). One contributing factor in differential biological outcomes is genomic architecture. Chromatin affects the accessibility of binding sites to natural transcription factors, but the extent to which polyamides are affected is unclear. Toward that end, we are developing a class of polyamides to directly identify binding sites in cells and reveal how chromatin architecture influences polyamide binding and expression of targeted genes.

Polyamide-DNA interactions in cells

246th National Meeting (2013)

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