  GC-rich sequences are recurring motifs in oncogenes and retroviruses, and
could be targeted by non-covalent major-groove therapeutic ligands. We
considered the palindromic sequence d(G1G2C3G4C5C6)2, and designed several
oligopeptide derivatives of the anti-cancer intercalator mitoxantrone. The
stability of their complexes with a 18-mer oligonucleotide encompassing this
sequence in its center was validated using polarizable molecular dynamics. We
report the most salient structural features of two novel compounds, having a
dialkylammonium group as a side-chain on both arms. The anthraquinone ring is
intercalated in the central d(CpG)2 sequence with its long axis perpendicular
to that of the two base-pairs. On each strand, this enables each ammonium group
to bind in-register to O6/N7 of the two facing G bases upstream. We
subsequently designed tris-intercalating derivatives, each dialkylammonium
substituted with a connector to an N9-aminoacridine intercalator extending our
target range from six- to a ten-base pair palindromic sequence,
d(C1G2G3G4C5G6C7C8C9G10)2. The structural features of the complex of the most
promising derivative are reported. The present design strategy paves the way
for designing intercalator-oligopeptide derivatives with an even higher
selectivity, targeting an increased number of DNA bases, going beyond ten.
