Preferred interaction of D-peptidyl-anthraquinones with double-stranded B-DNA.
The quest for more specific drugs in antitumor chemotherapy led us to the design of anthraquinone-peptide conjugates capable of selective recognition of the nucleic acid. We present here the DNA binding characteristics, sequence specificity and geometry of interaction of a pair of enantiomers containing the lysine-glycine dipeptide in the side chains. The D enantiomer binds right handed double stranded DNA more efficiently than the L form under all conditions tested. The source of higher binding affinity is not electrostatic in nature and rests in the more favorable hydrophobic contacts of the D-lysyl side chains in the drug-DNA complex. Both derivatives exhibit preference for alternating GC base sequences and intercalate into DNA in a threading mode as suggested by chiroptical and theoretical studies. The D enantiomer, being a peptidyl derivative that contains a non-natural amino acid, has the considerable advantage of being less susceptible to enzymatic hydrolysis and could therefore represent a lead compound for further development.
Gatto
B
B
Department of Pharmaceutical Sciences, University of Padova, Italy.
Zagotto
G
G
Sissi
C
C
Palumbo
M
M
D000880:Anthraquinones / Q000737:chemistry* / Q000378:metabolism; D001482:Base Composition; D001665:Binding Sites; D002942:Circular Dichroism; D004247:DNA / Q000737:chemistry* / Q000378:metabolism*; D008956:Models, Chemical; D010455:Peptides / Q000737:chemistry* / Q000378:metabolism; D013379:Substrate Specificity
D000880:Anthraquinones; D010455:Peptides; D004247:DNA