<br>G4 配体缀合的寡核苷酸介导个体 G4 DNA 结构的选择性结合和稳定,Journal of the American Chemical Society

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G4 配体缀合的寡核苷酸介导个体 G4 DNA 结构的选择性结合和稳定
Journal of the American Chemical Society ( IF 14.4 ) Pub Date : 2024-03-02 , DOI: 10.1021/jacs.3c14408
Andreas Berner ₁ , Rabindra Nath Das ₂ , Naresh Bhuma ₂ , Justyna Golebiewska ₂ , Alva Abrahamsson ₂ , Måns Andréasson ₂ , Namrata Chaudhari ₁ , Mara Doimo ₁ , Partha Pratim Bose ₃ , Karam Chand ₂ , Roger Strömberg ₃ , Sjoerd Wanrooij ₁ , Erik Chorell ₂

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G-四链体 (G4) DNA 结构是普遍存在的二级 DNA 结构，与复制和转录等基本细胞功能有关。此外，G4结构与癌症等人类疾病直接相关，并且因其调节致病基因（例如癌基因）的能力而被强调为有前途的治疗靶点。因此，结合并稳定这些结构的小分子从治疗角度来看很有价值，并且有助于研究 G4 结构的生物学功能。然而，人类基因组中有数十万个G4 DNA基序，该领域长期存在的一个问题是如何实现这些不同G4结构之间的特异性。在这里，我们开发了一种选择性靶向单个 G4 DNA 结构的策略。该策略基于无选择性地结合和稳定 G4 的配体，与引导寡核苷酸缀合，特异性引导 G4 配体缀合寡核苷酸 (GL-O) 至单一目标 G4 结构。通过采用各种生物物理和生化技术，我们表明所开发的方法能够靶向独特的、特定的 G4 结构，而不影响其他脱靶的 G4 形成。考虑到人类基因组中存在大量的 G4，这代表了一种研究单个 G4 的存在和功能的有前途的策略，但也可能具有作为未来治疗方式的潜力。

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G4-Ligand-Conjugated Oligonucleotides Mediate Selective Binding and Stabilization of Individual G4 DNA Structures

G-quadruplex (G4) DNA structures are prevalent secondary DNA structures implicated in fundamental cellular functions, such as replication and transcription. Furthermore, G4 structures are directly correlated to human diseases such as cancer and have been highlighted as promising therapeutic targets for their ability to regulate disease-causing genes, e.g., oncogenes. Small molecules that bind and stabilize these structures are thus valuable from a therapeutic perspective and helpful in studying the biological functions of the G4 structures. However, there are hundreds of thousands of G4 DNA motifs in the human genome, and a long-standing problem in the field is how to achieve specificity among these different G4 structures. Here, we developed a strategy to selectively target an individual G4 DNA structure. The strategy is based on a ligand that binds and stabilizes G4s without selectivity, conjugated to a guide oligonucleotide, that specifically directs the G4-Ligand-conjugated oligo (GL-O) to the single target G4 structure. By employing various biophysical and biochemical techniques, we show that the developed method enables the targeting of a unique, specific G4 structure without impacting other off-target G4 formations. Considering the vast amount of G4s in the human genome, this represents a promising strategy to study the presence and functions of individual G4s but may also hold potential as a future therapeutic modality.

更新日期：2024-03-02

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