Targeting the Major Groove of the Palindromic d(GGCGCC)2 Sequence by Oligopeptide Derivatives of Anthraquinone Intercalators - Inria - Institut national de recherche en sciences et technologies du numérique Access content directly
Journal Articles Journal of Chemical Information and Modeling Year : 2022

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

Abstract

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.

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Dates and versions

hal-03624169 , version 1 (30-03-2022)

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Krystel El Hage, Giovanni Ribaudo, Louis Lagardère, Alberto Ongaro, Philippe H. Kahn, et al.. Targeting the Major Groove of the Palindromic d(GGCGCC)2 Sequence by Oligopeptide Derivatives of Anthraquinone Intercalators. Journal of Chemical Information and Modeling, 2022, 62 (24), pp.6649-6666. ⟨10.1021/acs.jcim.2c00337⟩. ⟨hal-03624169⟩
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