Synthetic dsDNA-Binding Peptides Using Natural Compounds as Model

• Published in: Helvetica chimica acta 2006-06, Vol.89 (6), p.1194-1219
• Main Authors: Borgions, Filip, Ghyssels, Daniel, Van Aerschot, A., Rozenski, J., Herdewijn, Piet
• Format: Article
• Language: English
• Subjects: Acridine conjugates; DNA Binding; Ethidium bromide; Mass spectrometry; Peptides
• ISSN: 0018-019X; 1522-2675
• DOI: 10.1002/hlca.200690118

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 × 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 × 10−6 M), which is similar to the binding strength of the well‐known DNA binder Hoechst 33258.