Recognition of 16 base pairs in the minor groove of DNA by a pyrrole-imidazole polyamide dimer

Abstract

Cell-permeable small molecules that bind predetermined DNA sequences with affinities and specificities comparable to those of natural DNA-binding proteins have the potential to regulate the expression of specific genes. Recently, an eight-ring hairpin pyrrole-imidazole (Py-Im) polyamide which binds six base pairs of DNA was shown to inhibit transcription of a specific gene in cell culture. Polyamides recognizing longer DNA sequences should provide more specific biological activity. To specify a single site within the 3 billion base pair human genome, ligands which specifically recognize 15-16 base pairs are necessary. For this reason, recognition of 16 base pairs represents a milestone in the development of chemical approaches to DNA recognition. We examine here the affinity and specificity of a Py-Im polyamide dimer which targets 16 contiguous base pairs in the minor groove of DNA.