Optimization of the hairpin polyamide design for recognition of the minor groove of DNA

In order to optimize the hairpin design for ligands which bind the minor groove of DNA, a series of four pyrrole-imidazole polyamides substituted at the C-terminus with aliphatic amino acids have been prepared using solid phase synthetic methodology. Addition of a C-terminal beta-alanine residue is found to enhance both the DNA binding affinity and sequence specificity, while addition of a C-terminal glycine residue is found to reduce DNA binding affinity and sequence specificity. These effects are modulated by the addition of an N-terminal acetyl group. Insertion of a C-terminal aliphatic amino acid residue makes the hairpin polyamide motif compatible with solid phase synthetic methods, allowing the rapid design of new polyamides for high-affinity specific recognition of a broad sequence repertoire in the minor groove of DNA.