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GC-rich sequences are recurring motifs in oncogenes and retroviruses, andcould be targeted by non-covalent major-groove therapeutic ligands. Weconsidered the palindromic sequence d(G1G2C3G4C5C6)2, and designed severaloligopeptide derivatives of the anti-cancer intercalator mitoxantrone. Thestability of their complexes with a 18-mer oligonucleotide encompassing thissequence in its center was validated using polarizable molecular dynamics. Wereport the most salient structural features of two novel compounds, having adialkylammonium group as a side-chain on both arms. The anthraquinone ring isintercalated in the central d(CpG)2 sequence with its long axis perpendicularto that of the two base-pairs. On each strand, this enables each ammonium groupto bind in-register to O6/N7 of the two facing G bases upstream. Wesubsequently designed tris-intercalating derivatives, each dialkylammoniumsubstituted with a connector to an N9-aminoacridine intercalator extending ourtarget range from six- to a ten-base pair palindromic sequence,d(C1G2G3G4C5G6C7C8C9G10)2. The structural features of the complex of the mostpromising derivative are reported. The present design strategy paves the wayfor designing intercalator-oligopeptide derivatives with an even higherselectivity, targeting an increased number of DNA bases, going beyond ten.

Targeting the Major Groove of the Palindromic d(GGCGCC)2 Sequence by Oligopeptide Derivatives of Anthraquinone Intercalators