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Targeting the Major Groove of the Palindromic d(GGCGCC)2 Sequence by Oligopeptide Derivatives of Anthraquinone Intercalators
Journal of Chemical Information and Modeling ( IF 5.6 ) Pub Date : 2022-07-27 , DOI: 10.1021/acs.jcim.2c00337 Krystel El Hage 1 , Giovanni Ribaudo 2 , Louis Lagardère 3 , Alberto Ongaro 2 , Philippe H Kahn 4 , Luc Demange 5 , Jean-Philip Piquemal 3, 6 , Giuseppe Zagotto 7 , Nohad Gresh 3
Journal of Chemical Information and Modeling ( IF 5.6 ) Pub Date : 2022-07-27 , DOI: 10.1021/acs.jcim.2c00337 Krystel El Hage 1 , Giovanni Ribaudo 2 , Louis Lagardère 3 , Alberto Ongaro 2 , Philippe H Kahn 4 , Luc Demange 5 , Jean-Philip Piquemal 3, 6 , Giuseppe Zagotto 7 , Nohad Gresh 3
Affiliation
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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(G1G2C3G4C5C6)2, 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)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 a 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 even higher selectivity, targeting an increased number of DNA bases, going beyond ten.
中文翻译：
蒽醌嵌入剂的寡肽衍生物靶向回文 d(GGCGCC)2 序列的主要凹槽
富含 GC 的序列是癌基因和逆转录病毒中的重复基序，可以被非共价主沟治疗配体靶向。我们考虑了回文序列d(G 1 G 2 C 3 G 4 C 5 C 6 ) 2，并设计了几种抗癌嵌入剂米托蒽醌的寡肽衍生物。使用可极化分子动力学验证了它们与在其中心包含该序列的 18 聚体寡核苷酸的复合物的稳定性。我们报告了两种新型化合物最显着的结构特征，双臂上都有一个二烷基铵基团作为侧链。蒽醌环嵌入中央 d(CpG) 2其长轴垂直于两个碱基对的序列。在每条链上，这使每个铵基团能够在注册上绑定到上游两个面对的 G 碱基的 O 6 /N 7。我们随后设计了三嵌入衍生物，每个二烷基铵都被连接到N 9 -氨基吖啶嵌入剂的连接器取代，将我们的目标范围从六碱基对扩展到十碱基对回文序列，d(C 1 G 2 G 3 G 4 C 5 G 6 C 7 C 8 C 9 G 10 ) 2. 报道了最有前途的衍生物的复合物的结构特征。目前的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，目标是增加 DNA 碱基数量，超过 10 个。
更新日期：2022-07-27
中文翻译：
蒽醌嵌入剂的寡肽衍生物靶向回文 d(GGCGCC)2 序列的主要凹槽
富含 GC 的序列是癌基因和逆转录病毒中的重复基序，可以被非共价主沟治疗配体靶向。我们考虑了回文序列d(G 1 G 2 C 3 G 4 C 5 C 6 ) 2，并设计了几种抗癌嵌入剂米托蒽醌的寡肽衍生物。使用可极化分子动力学验证了它们与在其中心包含该序列的 18 聚体寡核苷酸的复合物的稳定性。我们报告了两种新型化合物最显着的结构特征，双臂上都有一个二烷基铵基团作为侧链。蒽醌环嵌入中央 d(CpG) 2其长轴垂直于两个碱基对的序列。在每条链上，这使每个铵基团能够在注册上绑定到上游两个面对的 G 碱基的 O 6 /N 7。我们随后设计了三嵌入衍生物，每个二烷基铵都被连接到N 9 -氨基吖啶嵌入剂的连接器取代，将我们的目标范围从六碱基对扩展到十碱基对回文序列，d(C 1 G 2 G 3 G 4 C 5 G 6 C 7 C 8 C 9 G 10 ) 2. 报道了最有前途的衍生物的复合物的结构特征。目前的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，目标是增加 DNA 碱基数量，超过 10 个。
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