Synthetic dsDNA‐Binding Peptides Using Natural Compounds as Model |
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Authors: | Filip Borgions Daniel Ghyssels A VanAerschot J Rozenski Piet Herdewijn |
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Institution: | Filip Borgions,Daniel Ghyssels,A. Van?Aerschot,J. Rozenski,Piet Herdewijn |
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Abstract: | 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. |
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Keywords: | Peptides DNA Binding Acridine conjugates Ethidium bromide Mass spectrometry |
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