Department of Medicinal Chemistry, Faculty of Pharmacy, Kerman University of Medical Sciences, Kerman, Iran (A.A., S.N.); Institut Pasteur, Department of Virology, UMR 3569 CNRS, Paris, France (M.L.); Faculty of Medicine, Kerman University of Medical Sciences, Kerman, Iran (M.R.); Dioscuri Center of Chromatin Biology and Epigenomics, Nencki Institute of Experimental Biology, Polish Academy of Sciences, Warsaw, Poland (P.Z.); Faculty of Medicine, Cardinal Stefan Wyszyński University in Warsaw, Warsaw, Poland (P.Z.); Laboratoire d'Optique et Biosciences, Ecole Polytechnique, CNRS, INSERM, Institut Polytechnique de Paris, Palaiseau cedex, France (J.-L.M.); Pharmaceutics Research Center, Institute of Neuropharmacology, Kerman University of Medical Sciences, Kerman, Iran (H.-R.R.); and Department of Pharmacology and Toxicology, Faculty of Pharmacy, Kerman University of Medical Sciences, Kerman, Iran (H.-R.R.).
Department of Medicinal Chemistry, Faculty of Pharmacy, Kerman University of Medical Sciences, Kerman, Iran (A.A., S.N.); Institut Pasteur, Department of Virology, UMR 3569 CNRS, Paris, France (M.L.); Faculty of Medicine, Kerman University of Medical Sciences, Kerman, Iran (M.R.); Dioscuri Center of Chromatin Biology and Epigenomics, Nencki Institute of Experimental Biology, Polish Academy of Sciences, Warsaw, Poland (P.Z.); Faculty of Medicine, Cardinal Stefan Wyszyński University in Warsaw, Warsaw, Poland (P.Z.); Laboratoire d'Optique et Biosciences, Ecole Polytechnique, CNRS, INSERM, Institut Polytechnique de Paris, Palaiseau cedex, France (J.-L.M.); Pharmaceutics Research Center, Institute of Neuropharmacology, Kerman University of Medical Sciences, Kerman, Iran (H.-R.R.); and Department of Pharmacology and Toxicology, Faculty of Pharmacy, Kerman University of Medical Sciences, Kerman, Iran (H.-R.R.)
Pharmacol Rev. 2021 Jul;73(3):897-923. doi: 10.1124/pharmrev.120.000230.
Guanine-rich DNA and RNA sequences can fold into noncanonical nucleic acid structures called G-quadruplexes (G4s). Since the discovery that these structures may act as scaffolds for the binding of specific ligands, G4s aroused the attention of a growing number of scientists. The versatile roles of G4 structures in viral replication, transcription, and translation suggest direct applications in therapy or diagnostics. G4-interacting molecules (proteins or small molecules) may also affect the balance between latent and lytic phases, and increasing evidence reveals that G4s are implicated in generally suppressing viral processes, such as replication, transcription, translation, or reverse transcription. In this review, we focus on the discovery of G4s in viruses and the role of G4 ligands in the antiviral drug discovery process. After assessing the role of viral G4s, we argue that host G4s participate in immune modulation, viral tumorigenesis, cellular pathways involved in virus maturation, and DNA integration of viral genomes, which can be potentially employed for antiviral therapeutics. Furthermore, we scrutinize the impediments and shortcomings in the process of studying G4 ligands and drug discovery. Finally, some unanswered questions regarding viral G4s are highlighted for prospective future projects. SIGNIFICANCE STATEMENT: G-quadruplexes (G4s) are noncanonical nucleic acid structures that have gained increasing recognition during the last few decades. First identified as relevant targets in oncology, their importance in virology is now increasingly clear. A number of G-quadruplex ligands are known: viral transcription and replication are the main targets of these ligands. Both viral and cellular G4s may be targeted; this review embraces the different aspects of G-quadruplexes in both host and viral contexts.
富含鸟嘌呤的 DNA 和 RNA 序列可以折叠成称为 G-四链体 (G4) 的非经典核酸结构。自从发现这些结构可以作为特定配体结合的支架以来，G4 引起了越来越多的科学家的关注。G4 结构在病毒复制、转录和翻译中的多功能作用表明它们在治疗或诊断中有直接的应用。G4 结构相互作用的分子（蛋白质或小分子）也可能影响潜伏和裂解阶段之间的平衡，越来越多的证据表明 G4 参与普遍抑制病毒过程，例如复制、转录、翻译或逆转录。在这篇综述中，我们专注于病毒中 G4 的发现以及 G4 配体在抗病毒药物发现过程中的作用。在评估了病毒 G4 的作用后，我们认为宿主 G4 参与免疫调节、病毒肿瘤发生、参与病毒成熟的细胞途径以及病毒基因组的 DNA 整合，这些都可以潜在地用于抗病毒治疗。此外，我们仔细研究了研究 G4 配体和药物发现过程中的障碍和缺点。最后，突出了关于病毒 G4 的一些未解决的问题，以供未来项目参考。
G-四链体 (G4) 是非经典核酸结构，在过去几十年中越来越受到关注。首先被确定为肿瘤学中的相关靶点，它们在病毒学中的重要性现在越来越明显。已经知道了一些 G-四链体配体：这些配体的主要靶点是病毒转录和复制。既可以靶向病毒和细胞 G4，本综述涵盖了宿主和病毒环境中 G4 的不同方面。
