Subtle recognition of 14-base pair DNA sequences via threading polyintercalation.

Small molecules that bind DNA in a sequence-specific manner could act as antibiotic, antiviral, or anticancer agents because of their potential ability to manipulate gene expression. Our laboratory has developed threading polyintercalators based on 1,4,5,8-naphthalene diimide (NDI) units connected in a head-to-tail fashion by flexible peptide linkers. Previously, a threading tetraintercalator composed of alternating minor-major-minor groove-binding modules was shown to bind specifically to a 14 bp DNA sequence with a dissociation half-life of 16 days [Holman, G.

A sequence-specific threading tetra-intercalator with an extremely slow dissociation rate constant.

A long-lived and sequence-specific ligand-DNA complex would make possible the modulation of biological processes for extended periods. For this purpose, we are investigating a polyintercalation approach to DNA recognition in which flexible chains of aromatic units thread back and forth repeatedly through the double helix. Here we describe the DNA-binding behaviour of a threading tetra-intercalator.