Interaction of DNA-threading peptide-amsacrine conjugates with DNA and chromatin.
The SPKK peptide motif which functions as a DNA minor groove binding unit in various chromosomal and gene regulatory proteins has been attached to the antitumour drug amsacrine in order to reinforce interaction with DNA. Two bifunctional molecules in which an amsacrine-4-carboxamide derivative is linked to one or two SPKK motifs via a diaminopropyl tether have been designed and synthesized. We have applied various spectroscopic methods (absorption, circular and linear dichroism) to delineate the role of the peptide moiety as opposed to the chromophoric acridine moiety in the interaction of the conjugates with both DNA and chromatin. The structural and kinetic data concur that the two peptide conjugates thread through the DNA double helix so as to intercalate their acridine chromophore, leaving the SPKK motif and the methanesulphonanilino group positioned within the minor and major grooves of the double helix respectively. The threading-type intercalation process, evidenced by stopped-flow measurements, is not affected when the DNA is wrapped around histones. Linkage of the SPKK peptide motif to intercalating drugs represents an efficient system to stabilize drug-DNA complexes.
Bourdouxhe-Housiaux
C
C
Laboratoire de Chimie Macromoléculaire et Chimie Physique, Université de Liège, Belgium.
Colson
P
P
Houssier
C
C
Bailly
C
C
D000677:Amsacrine / Q000378:metabolism*; D002843:Chromatin / Q000378:metabolism*; D002942:Circular Dichroism; D004247:DNA / Q000378:metabolism*; D007700:Kinetics; D010455:Peptides / Q000737:chemistry / Q000378:metabolism*; D013056:Spectrophotometry, Ultraviolet
D002843:Chromatin; D010455:Peptides; D000677:Amsacrine; D004247:DNA