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

Abstract

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 β-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.