Department of Chemistry , Indian Institute of Technology Bombay , Mumbai 400076 , India.
Okinawa Institute of Science and Technology Graduate University , Okinawa 9040495 , Japan.
ACS Chem Biol. 2019 Oct 18;14(10):2102-2114. doi: 10.1021/acschembio.9b00475. Epub 2019 Oct 4.
G-Quadruplexes (G4s) are four-stranded nucleic acid structures whose underlying G-rich sequences are present across the chromosome and transcriptome. These highly structured elements are known to regulate many key biological functions such as replication, transcription, translation, and genomic stability, thereby providing an additional layer of gene regulation. G4s are structurally dynamic and diverse, and they can fold into numerous topologies. They are potential targets for small molecules, which can modulate their functions. To this end, myriad classes of small molecules have been developed and studied for their ability to bind and stabilize these unique structures. Though many of them can selectively target G4s over duplex DNA, only a few of them can distinguish one G4 topology from others. Design and development of G4-specific ligands are challenging owing to the subtle structural variations among G4 structures. However, screening assays and computational methods have identified a few classes of ligands that preferentially or specifically target the G4 topology of interest over others. This review focuses on the small molecules and fluorescent probes that specifically target human promoter G4s associated with oncogenes. Targeting promoter G4s could circumvent the issues such as undruggability and development of drug resistance associated with the protein targets. The ligands discussed here highlight that development of G4-specific ligands is an achievable goal in spite of the limited structural data available. The future goal is to pursue the development of G4-specific ligands endowed with drug-like properties for G4-based therapeutics and diagnostics.
四链体（G4s）是由富含鸟嘌呤的序列组成的四链核酸结构，这些序列在染色体和转录组中普遍存在。这些高度结构化的元件已知可以调节许多关键的生物学功能，如复制、转录、翻译和基因组稳定性，从而提供了额外的基因调控层。G4s 结构动态且多样化，可以折叠成多种拓扑结构。它们是小分子的潜在靶点，可以调节它们的功能。为此，已经开发并研究了无数类小分子，以研究它们结合和稳定这些独特结构的能力。尽管其中许多小分子可以选择性地靶向 G4 而不是双链 DNA，但只有少数小分子可以区分一种 G4 拓扑结构与其他结构。由于 G4 结构之间存在细微的结构差异，因此设计和开发 G4 特异性配体具有挑战性。然而，筛选测定和计算方法已经确定了几类配体，它们可以优先或特异性地靶向感兴趣的 G4 拓扑结构，而不是其他结构。本综述重点介绍了专门针对与癌基因相关的人类启动子 G4 的小分子和荧光探针。靶向启动子 G4 可以规避与蛋白质靶标相关的不可成药性和耐药性发展等问题。这里讨论的配体强调，尽管可用的结构数据有限，但开发 G4 特异性配体是一个可行的目标。未来的目标是追求开发具有类药性的 G4 特异性配体，用于基于 G4 的治疗和诊断。
