Acta Chim Slov. 2020 Sep;67(3):683-700.
G-quadruplexes (G4s) are noncanonical secondary structures that fold within guanine (G) rich strands of regulatory genomic regions. Recent evidences suggest their intimate involvement in important biological processes such as telomere maintenance, end-capping and protection, chromosome stability, gene expression, viral integration, and recombination. Mechanistic details of how and why G4 structures influence biological function indicate a rationale for treating G4s as emerging molecular targets for future therapeutics. In other words, the structural heterogeneity with well-defined binding sites, thermal stability and abundance of G4s in telomeres, oncogene promoter regions, and viral genomes make G4s attractive targets for small molecules, aimed to selectively recognize them over all other nucleic acids structures, particularly duplex forms that are most abundant in the genome. Herein, a critical survey of well-characterized G4-interactive ligands as potential tools in anti-cancer and antiviral therapies is presented. Effects that these ligands selectively exert in vitro and in vivo models are summarized. Unique ligands involved in specific G4 recognition are put forward. A key question, how to design and develop new G4 specific ligands that conform to the structural and physicochemical requirements for optimal biological activity, is discussed by considering both remarkable advances over the last few years and our recent contributions.
四链体（G4s）是一种非典型的二级结构，可在富含鸟嘌呤（G）的调节基因组区域的链中折叠。最近的证据表明，它们密切参与重要的生物学过程，如端粒维持、端粒加帽和保护、染色体稳定性、基因表达、病毒整合和重组。G4 结构如何以及为什么影响生物学功能的机制细节表明，将 G4 视为未来治疗的新兴分子靶标是合理的。换句话说，结构异质性具有明确的结合位点、热稳定性和端粒、癌基因启动子区域和病毒基因组中 G4 的丰度，使 G4 成为小分子的有吸引力的靶标，旨在选择性地识别它们而不是其他所有核酸结构，特别是在基因组中最丰富的双链形式。在此，本文对经过充分表征的 G4 相互作用配体作为抗癌和抗病毒治疗的潜在工具进行了批判性调查。总结了这些配体在体外和体内模型中选择性发挥的作用。提出了涉及特定 G4 识别的独特配体。通过考虑过去几年的显著进展和我们最近的贡献，讨论了如何设计和开发符合最佳生物学活性的结构和物理化学要求的新型 G4 特异性配体这一关键问题。
