Pérez-Soto Manuel, Peñalver Pablo, Muñoz-Báez Paloma, Tolosa Juan, García-Martínez Joaquín Calixto, Cebrián Rubén, Morales Juan Carlos
Departamento de Bioquímica y Farmacología Molecular, Instituto de Parasitología y Biomedicina López Neyra, CSIC, PTS Granada, Avenida del Conocimiento 17, 18016 Armilla, Spain.
Department of Clinical Microbiology, Instituto de Investigación Biosanitaria ibs. GRANADA, University Hospital Clínico San Cecilio, Av. de la Innovación s/n, 18061 Granada, Spain.
Molecules. 2024 Dec 12;29(24):5875. doi: 10.3390/molecules29245875.
G-quadruplexes (G4s) are non-canonical secondary structures that play a crucial role in the regulation of genetic expression. This study explores the interaction between G4s and a small family of oligostyrylbenzene (OSB) derivatives, characterized by tris(styryl)benzene and tetrastyrylbenzene backbones, functionalized with either trimethylammonium or 1-methylpyridinium groups. Initially identified as DNA ligands, these OSB derivatives have now been recognized as potent G4 binders, surpassing in binding affinity commercially available ligands such as pyridostatin and displaying good selectivity for G4s over duplex DNA. Furthermore, OSB derivatives and demonstrated significant antiparasitic activity against bloodstream forms of and extracellular , with high selectivity indices when compared to MRC-5 healthy control cells. Derivatives and exhibited moderate biocidal effects against a range of Gram-positive and Gram-negative bacterial strains. Notably, a synergistic antibacterial effect was observed when these compounds were combined with traditional antibiotics, particularly against , highlighting their potential utility in addressing drug-resistant bacterial infections. The differences in bioactivity among the OSB derivatives can be attributed to variations in cellular uptake, as proved by flow cytometry analysis. This suggests that the degree of cellular internalization plays a pivotal role in the observed antiparasitic and antibacterial efficacy.
G-四链体（G4s）是非经典二级结构，在基因表达调控中发挥关键作用。本研究探讨了G4s与一小类寡聚芪苯（OSB）衍生物之间的相互作用，这些衍生物以三（苯乙烯基）苯和四苯乙烯基苯为主链，并分别用三甲基铵或1-甲基吡啶鎓基团进行功能化修饰。这些OSB衍生物最初被鉴定为DNA配体，现在已被公认为有效的G4结合剂，其结合亲和力超过了诸如吡啶抑素等市售配体，并且对G4s的选择性优于双链DNA。此外，OSB衍生物 和 对布氏锥虫的血流形式和细胞外的克氏锥虫表现出显著的抗寄生虫活性，与MRC-5健康对照细胞相比具有高选择性指数。衍生物 和 对一系列革兰氏阳性和革兰氏阴性细菌菌株表现出中等的杀菌作用。值得注意的是，当这些化合物与传统抗生素联合使用时，观察到了协同抗菌作用，特别是对 ，突出了它们在解决耐药细菌感染方面的潜在效用。流式细胞术分析证明，OSB衍生物之间生物活性的差异可归因于细胞摄取的变化。这表明细胞内化程度在观察到的抗寄生虫和抗菌功效中起关键作用。
