DNA guanine (G)-quadruplexes (G4s) are unique secondary structures formed by two or more stacked G-tetrads in G-rich DNA sequences. These structures have been found to play a crucial role in highly transcribed genes, especially in cancer-related oncogenes, making them attractive targets for cancer therapeutics. Significantly, targeting oncogene promoter G4 structures has emerged as a promising strategy to address the challenge of undruggable and drug-resistant proteins, such as MYC, BCL2, KRAS, and EGFR. Natural products have long been an important source of drug discovery, particularly in the fields of cancer and infectious diseases. Noteworthy progress has recently been made in the discovery of naturally occurring DNA G4-targeting drugs. Numerous DNA G4s, such as MYC-G4, BCL2-G4, KRAS-G4, PDGFR-β-G4, VEGF-G4, and telomeric-G4, have been identified as potential targets of natural products, including berberine, telomestatin, quindoline, sanguinarine, isaindigotone, and many others. Herein, we summarize and evaluate recent advancements in natural and nature-derived DNA G4 binders, focusing on understanding the structural recognition of DNA G4s by small molecules derived from nature. We also discuss the challenges and opportunities associated with developing drugs that target DNA G4s.

中文翻译：

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DNA G-四链体作为天然产物药物发现的靶标


DNA 鸟嘌呤 （G）-四链体 （G4） 是由富含 G 的 DNA 序列中的两个或多个堆叠的 G-四链体形成的独特二级结构。已发现这些结构在高度转录的基因中起着至关重要的作用，尤其是在癌症相关癌基因中，使其成为癌症治疗的有吸引力的靶标。值得注意的是，靶向癌基因启动子 G4 结构已成为解决不可成药和耐药蛋白（如 MYC、BCL2、KRAS 和 EGFR）挑战的一种有前途的策略。长期以来，天然产物一直是药物发现的重要来源，尤其是在癌症和传染病领域。最近在发现天然存在的 DNA G4 靶向药物方面取得了显着进展。许多 DNA G4，如 MYC-G4、BCL2-G4、KRAS-G4、PDGFR-β-G4、VEGF-G4 和端粒-G4，已被确定为天然产物的潜在靶标，包括小檗碱、端美他汀、喹哚啉、血根碱、爱蓝黛酮等。在此，我们总结和评估了天然和天然来源的 DNA G4 结合剂的最新进展，重点是了解自然来源的小分子对 DNA G4 的结构识别。我们还讨论了与开发靶向 DNA G4 的药物相关的挑战和机遇。