i-Motifs and G-quadruplexes are dynamic nucleic acid secondary structures, which are believed to play key roles in gene expression. We herein report two peptidomimetic ligands (PBP1 and PBP2) that selectively target i-motifs and G-quadruplexes over double-stranded DNA. These peptidomimetics, regioisomeric with respect to the position of triazole/prolinamide motifs, have been synthesized using a modular method involving Cu(I)-catalyzed azide and alkyne cycloaddition. The para-isomer, PBP1 exhibits high selectivity for i-motifs while the meta-isomer PBP2 binds selectively to G-quadruplex structures. Interestingly, these ligands have the ability to induce G-quadruplex or i-motif structures from the unstructured single-stranded DNA conformations, as observed using single molecule Förster resonance energy transfer (smFRET) studies. The quantitative real-time polymerase chain reaction (qRT-PCR), western blot, and dual-luciferase assays indicate that PBP1 upregulates and PBP2 downregulates BCL-2 gene expression in cancer cells.

中文翻译：

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小分子优先靶向i-基序和G-四链体

i-基序和G-四链体是动态核酸二级结构，据信在基因表达中起关键作用。我们在此报告了两个拟肽配体（PBP1和PBP2），它们选择性地在双链DNA上靶向i-基序和G-四链体。这些肽模拟物，相对于三唑/脯氨酰胺基序的位置是区域异构的，已经使用涉及Cu（I）催化的叠氮化物和炔烃环加成的模块化方法合成。对位异构体PBP1对i-基元具有高选择性，而对位异构体PBP2选择性结合到G-四链体结构。有趣的是，如使用单分子Förster共振能量转移（smFRET）研究所观察到的，这些配体具有从非结构化单链DNA构象诱导G-四链体或i-基序结构的能力。定量实时聚合酶链反应（qRT-PCR），蛋白质印迹和双荧光素酶测定表明，PBP1上调而PBP2下调癌细胞中的BCL-2基因表达。