BMPQ-1 binds selectively to (3+1) hybrid topologies in human telomeric G-quadruplex multimers.
BMPQ-1 binds selectively to (3+1) hybrid topologies in human telomeric G-quadruplex multimers.
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BMPQ-1 选择性结合人端粒 G-四链体多聚体中的 (3 1) 混合拓扑。
DOI：
10.1093/nar/gkaa870
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发表时间：
2020-11-18
影响因子：
14.9
通讯作者：
Wei D
中科院分区：
文献类型：
--
作者：
Gao C;Liu Z;Hou H;Ding J;Chen X;Xie C;Song Z;Hu Z;Feng M;Mohamed HI;Xu S;Parkinson GN;Haider S;Wei D
来自人类端粒的单个G-四链体形成序列可以采用在生理条件下可相互转换的六种不同拓扑结构。这对设计对特定构象显示选择性和特异性的配体提出了挑战。在区分多聚体G-四链体与单体物质时引入了额外的复杂性，单体物质将能够在端粒的单链3′端形成。已经报道了一些配体与二聚体四链体结合，但其临床前药理学评价有限。利用多学科的方法，我们确定了一种新的喹啉核心配体，BMPQ-1，它结合到人类端粒的G-四链体多聚体单体G-四链体具有高选择性，并诱导G-四链体DNA的形成沿着在端粒相关的DNA损伤反应。BMPQ-1抑制肿瘤细胞增殖，IC 50为1.0 μM，小鼠肿瘤生长速率减半。使用smFRET的生物物理分析确定了在溶液中共存的二聚G-四链体的多种构象的混合物。在这里，我们表明BMPQ-1的滴定将多聚体G-四链体的构象整体向（3+1）杂合-2拓扑结构转移，随着进一步的G-四链体单元的加入，这变得更加明显。
A single G-quadruplex forming sequence from the human telomere can adopt six distinct topologies that are inter-convertible under physiological conditions. This presents challenges to design ligands that show selectivity and specificity towards a particular conformation. Additional complexity is introduced in differentiating multimeric G-quadruplexes over monomeric species, which would be able to form in the single-stranded 3′ ends of telomeres. A few ligands have been reported that bind to dimeric quadruplexes, but their preclinical pharmacological evaluation is limited. Using multidisciplinary approaches, we identified a novel quinoline core ligand, BMPQ-1, which bound to human telomeric G-quadruplex multimers over monomeric G-quadruplexes with high selectivity, and induced the formation of G-quadruplex DNA along with the related DNA damage response at the telomere. BMPQ-1 reduced tumor cell proliferation with an IC50 of ∼1.0 μM and decreased tumor growth rate in mouse by half. Biophysical analysis using smFRET identified a mixture of multiple conformations coexisting for dimeric G-quadruplexes in solution. Here, we showed that the titration of BMPQ-1 shifted the conformational ensemble of multimeric G-quadruplexes towards (3+1) hybrid-2 topology, which became more pronounced as further G-quadruplex units are added.
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影响因子：
15
作者：
Davis, Dexter C.;Hoch, Dominic G.;Dai, Mingji
通讯作者：
Dai, Mingji
DOI：
10.1002/anie.201605350
发表时间：
2016-08-22
期刊：
Angewandte Chemie (International ed. in English)
影响因子：
--
作者：
Bončina M;Vesnaver G;Chaires JB;Lah J
通讯作者：
Lah J
影响因子：
14.9
作者：
Bianchi F;Comez L;Biehl R;D'Amico F;Gessini A;Longo M;Masciovecchio C;Petrillo C;Radulescu A;Rossi B;Sacchetti F;Sebastiani F;Violini N;Paciaroni A
通讯作者：
Paciaroni A
影响因子：
14.9
作者：
Lane AN;Chaires JB;Gray RD;Trent JO
通讯作者：
Trent JO
新的喹喔啉取代物通过特异性下调 c-MYC 转录来抑制三阴性乳腺癌
影响因子：
14.9
作者：
Hu, Ming-Hao;Wu, Tian-Ying;Jin, Guangyi
通讯作者：
Jin, Guangyi