PDF(Pubmed)
Abstract：
The concept of a mild mutagen was coined to describe a minor mutagenic activity exhibited by some nucleoside analogues that potentiated their efficacy as antiretroviral agents. In the present study, we report the mild mutagen activity of sofosbuvir (SOF) for hepatitis C virus (HCV). Serial passages of HCV in human hepatoma cells, in the presence of SOF at a concentration well below its cytotoxic concentration 50 (CC50) led to pre-extinction populations whose mutant spectra exhibited a significant increase of C→U transitions, relative to populations passaged in the absence of SOF. This was reflected in an increase in several diversity indices that were used to characterize viral quasispecies. The mild mutagenic activity of SOF was largely absent when it was tested with isogenic HCV populations that displayed high replicative fitness. Thus, SOF can act as a mild mutagen for HCV, depending on HCV fitness. Possible mechanisms by which the SOF mutagenic activity may contribute to its antiviral efficacy are discussed.
摘要：
提出了轻度诱变剂的概念，以描述一些核苷类似物表现出的较小的诱变活性，从而增强了其作为抗逆转录病毒药物的功效。在本研究中,我们报道了索非布韦（SOF）对丙型肝炎病毒（HCV）的轻度诱变活性。HCV在人肝癌细胞中的连续传代，在浓度远低于其细胞毒性浓度50（CC50）的SOF存在下，导致了灭绝前种群的突变光谱显示出C→U跃迁的显着增加，相对于在没有SOF的情况下传代的群体。这反映在用于表征病毒准种的几种多样性指数的增加中。当用表现出高复制适应性的等基因HCV群体进行测试时，SOF的轻度诱变活性基本上不存在。因此，SOF可以作为HCV的轻度诱变剂，取决于HCV的适应性。讨论了SOF诱变活性可能有助于其抗病毒功效的可能机制。
