SABNP, Univ Evry, INSERM U1204, Université Paris-Saclay, 91000 Evry, France.
Dipartimento di Medicina Molecolare e Traslazionale, Universita degli Studi di Brescia, 25123 Brescia, Italy.
J Chem Inf Model. 2022 Dec 26;62(24):6649-6666. doi: 10.1021/acs.jcim.2c00337. Epub 2022 Jul 27.
GC-rich sequences are recurring motifs in oncogenes and retroviruses and could be targeted by noncovalent major-groove therapeutic ligands. We considered the palindromic sequence d(GGCGCC), and designed several oligopeptide derivatives of the anticancer intercalator mitoxantrone. The stability of their complexes with an 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) 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 O/N of the two facing G bases upstream. We subsequently designed tris-intercalating derivatives, each dialkylammonium substituted with a connector to an -aminoacridine intercalator extending our target range from a six- to a ten-base-pair palindromic sequence, d(CGGGCGCCCG). 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 even higher selectivity, targeting an increased number of DNA bases, going beyond ten.
富含 GC 的序列是癌基因和逆转录病毒中的重复基序，可被非共价的大沟治疗性配体靶向。我们考虑了回文序列 d(GGCGCC)，并设计了几种抗癌嵌入剂米托蒽醌的寡肽衍生物。使用极化分子动力学验证了它们与包含该序列中心的 18 个核苷酸寡聚核苷酸形成复合物的稳定性。我们报告了两种新型化合物的最显著结构特征，它们在每个臂上都有一个二烷基铵基团作为侧链。蒽醌环与两条链上的 d(CpG)序列交错排列，其长轴垂直于两个碱基对。在每条链上，这使得每个铵基团都可以与上游两个面对的 G 碱基的 O/N 结合。随后，我们设计了三嵌入剂衍生物，每个二烷基铵基团都用连接器取代了一个 -氨基吖啶嵌入剂，将我们的靶标范围从六碱基对到十碱基对回文序列 d(CGGGCGCCCG)扩展。报告了最有前途的衍生物复合物的结构特征。该设计策略为设计具有更高选择性的嵌入剂-寡肽衍生物铺平了道路，能够靶向更多的 DNA 碱基，超过十个。
