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Synthetic dsDNA‐Binding Peptides Using Natural Compounds as Model
Author(s) -
Borgions Filip,
Ghyssels Daniel,
Van Aerschot A.,
Rozenski J.,
Herdewijn Piet
Publication year - 2006
Publication title -
helvetica chimica acta
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.74
H-Index - 82
eISSN - 1522-2675
pISSN - 0018-019X
DOI - 10.1002/hlca.200690118
Subject(s) - chemistry , acridine , ethidium bromide , affinities , binding affinities , linker , stereochemistry , oligopeptide , dipeptide , dna , peptide , fluorescence , binding site , binding selectivity , amino acid , lysine , combinatorial chemistry , biochemistry , organic chemistry , physics , receptor , quantum mechanics , computer science , operating system
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‐NH 2 and Ac‐Arg‐Cbg‐Cha‐Chi‐Chi‐Tal‐Arg‐NH 2 . 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.