Bonnac Laurent F, Dreis Christine D, Rai Madhu, Geraghty Robert J
Center for Drug Design, College of Pharmacy, University of Minnesota, Minneapolis, MN 55455, USA.
Molecules. 2025 Jan 7;30(2):210. doi: 10.3390/molecules30020210.
Every year, dengue virus affects hundreds of millions of individuals worldwide. To date, there is no specific medication to treat dengue virus infections. Nucleobases, the base of a nucleoside without ribose, are understudied as potential treatments for viral infections. Antiviral nucleobases are converted in infected cells to their corresponding nucleoside triphosphate active form. Importantly, the conversion of nucleobases to their active nucleotide form and their antiviral effect can be enhanced when combined with de novo nucleotide biosynthesis inhibitors. In this work, we evaluated seven purine and pyrimidine nucleobases alone or combined with six purine or pyrimidine de novo nucleotide biosynthesis inhibitors, including novel prodrugs. Our study revealed that while a strong potentiation of purine nucleobases by purine de novo nucleotide biosynthesis inhibitors was observed, the pyrimidine nucleobases were not potentiated by pyrimidine de novo nucleotide biosynthesis inhibitors, possibly highlighting a significant difference between the modulation of purine versus pyrimidine de novo pathways and their impact on nucleobase potentiation. Most significant antiviral effects and potentiation were observed for Favipiravir, T-1105, and ribavirin nucleobases combined with purine nucleotide de novo synthesis inhibitors. These results are significant because drug combinations may solve the limited efficacy observed for some antiviral nucleobase drugs such as Favipiravir.
每年，登革热病毒都会影响全球数亿人。迄今为止，尚无治疗登革热病毒感染的特效药物。核碱基是没有核糖的核苷的碱基，作为病毒感染的潜在治疗方法，其研究较少。抗病毒核碱基在受感染细胞中转化为相应的核苷三磷酸活性形式。重要的是，当与从头合成核苷酸抑制剂联合使用时，核碱基向其活性核苷酸形式的转化及其抗病毒作用可以增强。在这项工作中，我们评估了七种嘌呤和嘧啶核碱基单独使用或与六种嘌呤或嘧啶从头合成核苷酸抑制剂（包括新型前药）联合使用的情况。我们的研究表明，虽然观察到嘌呤从头合成核苷酸抑制剂对嘌呤核碱基有很强的增效作用，但嘧啶核碱基并未被嘧啶从头合成核苷酸抑制剂增效，这可能突出了嘌呤与嘧啶从头合成途径的调节及其对核碱基增效作用影响之间的显著差异。对于法匹拉韦、T - 1105和利巴韦林核碱基与嘌呤核苷酸从头合成抑制剂联合使用，观察到了最显著的抗病毒效果和增效作用。这些结果意义重大，因为药物组合可能解决一些抗病毒核碱基药物（如法匹拉韦）疗效有限的问题。
