Rigo Riccardo, Groaz Elisabetta, Sissi Claudia
Department of Pharmaceutical and Pharmacological Sciences, University of Padova, Marzolo 5, 35131 Padova, Italy.
CEITEC-Central European Institute of Technology, Masaryk University, Kamenice 753/5, 625 00 Brno, Czech Republic.
Pharmaceuticals (Basel). 2022 Mar 19;15(3):373. doi: 10.3390/ph15030373.
In the past two decades, significant efforts have been put into designing small molecules to target selected genomic sites where DNA conformational rearrangements control gene expression. G-rich sequences at oncogene promoters are considered good points of intervention since, under specific environmental conditions, they can fold into non-canonical tetrahelical structures known as G-quadruplexes. However, emerging evidence points to a frequent lack of correlation between small molecule targeting of G-quadruplexes at gene promoters and the expression of the associated protein, which hampers pharmaceutical applications. The wide genomic localization of G-quadruplexes along with their highly polymorphic behavior may account for this scenario, suggesting the need for more focused drug design strategies. Here, we will summarize the G4 structural features that can be considered to fulfill this goal. In particular, by comparing a telomeric sequence with the well-characterized G-rich domain of the promoter, we will address how multiple secondary structures might cooperate to control genome architecture at a higher level. If this holds true, the link between drug-DNA complex formation and the associated cellular effects will need to be revisited.
在过去二十年中，人们付出了巨大努力来设计小分子，以靶向特定的基因组位点，这些位点的DNA构象重排控制着基因表达。癌基因启动子处富含G的序列被认为是很好的干预靶点，因为在特定环境条件下，它们可以折叠成称为G-四链体的非经典四螺旋结构。然而，新出现的证据表明，小分子靶向基因启动子处的G-四链体与相关蛋白质的表达之间常常缺乏相关性，这阻碍了药物应用。G-四链体在基因组中的广泛定位及其高度多态的行为可能是造成这种情况的原因，这表明需要更有针对性的药物设计策略。在这里，我们将总结为实现这一目标可考虑的G4结构特征。特别是，通过将端粒序列与特征明确的启动子富含G的结构域进行比较，我们将探讨多种二级结构如何协同作用以在更高水平上控制基因组结构。如果确实如此，药物与DNA复合物形成与相关细胞效应之间的联系将需要重新审视。
