Synthetic dsDNA-binding peptides using natural compounds as model

We have developed a series of short DNA-binding peptides containing newly synthesized, unnatural as well as natural amino acid building blocks. By a combinatorial-library approach, oligopeptides were developed with moderate dsDNA-binding affinities. Two strategies were used to further enhance the binding affinity of the lead peptides: Ac-Arg-Ual-Sar-Chi-Chi-Chi-Arg-NH2 and Ac-Arg-Cbg-Cha-Chi-Chi-Tal-Arg-NH2- Site-selective amino acid substitutions increased the binding affinities up to 2 x 10(-5) m. Further enhancement of the binding affinities could be achieved by coupling of an acridine intercalating unit, using linker arms of different length and flexibility. With the introduction of a new lysine-based acridine unit, different types of oligopeptide-acridine conjugates were designed using known dsDNA-binding ligands as model compounds. The binding capacities of these new oligopeptide-acridine conjugates have been investigated by a fluorescent intercalator (ethidium bromide) displacement (FID) assay. With the synthesis of the dipeptide-acridine conjugates, binding affinities in the low micromolar range were obtained (6.4 x 10(-6) m), which is similar to the binding Strength of the well-known DNA binder Hoechst 33258.status: publishe