Okesli Ayse, Khosla Chaitan, Bassik Michael C
Departments of Chemistry, Genetics, and Chemical Engineering, and Stanford ChEM-H, Stanford University, Stanford, CA 94305, United States.
Departments of Chemistry, Genetics, and Chemical Engineering, and Stanford ChEM-H, Stanford University, Stanford, CA 94305, United States.
Curr Opin Biotechnol. 2017 Dec;48:127-134. doi: 10.1016/j.copbio.2017.03.010. Epub 2017 Apr 27.
The development of broad-spectrum, host-acting antiviral therapies remains an important but elusive goal in anti-infective drug discovery. To replicate efficiently, viruses not only depend on their hosts for an adequate supply of pyrimidine nucleotides, but also up-regulate pyrimidine nucleotide biosynthesis in infected cells. In this review, we outline our understanding of mammalian de novo and salvage metabolic pathways for pyrimidine nucleotide biosynthesis. The available spectrum of experimental and FDA-approved drugs that modulate individual steps in these metabolic pathways is also summarized. The logic of a host-acting combination antiviral therapy comprised of inhibitors of dihydroorotate dehydrogenase and uridine/cytidine kinase is discussed.
开发广谱、作用于宿主的抗病毒疗法仍然是抗感染药物研发中一个重要但难以实现的目标。为了高效复制，病毒不仅依赖宿主提供充足的嘧啶核苷酸供应，还会上调感染细胞中嘧啶核苷酸的生物合成。在这篇综述中，我们概述了我们对哺乳动物嘧啶核苷酸生物合成的从头合成和补救代谢途径的理解。还总结了调节这些代谢途径中各个步骤的现有实验性药物和FDA批准药物的范围。讨论了由二氢乳清酸脱氢酶抑制剂和尿苷/胞苷激酶组成的作用于宿主的联合抗病毒疗法的原理。
