KU Leuven, Rega Institute for Medical Research, Herestraat 49, B-3000 Leuven, Belgium; University of Hamburg, Faculty of Sciences, Department of Chemistry, Organic Chemistry, Martin-Luther-King-Platz 6, D-20146 Hamburg, Germany.
KU Leuven, Rega Institute for Medical Research, Herestraat 49, B-3000 Leuven, Belgium.
Antiviral Res. 2019 Jul;167:1-5. doi: 10.1016/j.antiviral.2019.04.002. Epub 2019 Apr 2.
The antiviral drug T-705 (favipiravir) and its non-fluorinated analogue T-1105 inhibit the polymerases of RNA viruses after being converted to their ribonucleoside triphosphate (RTP) metabolite. We here compared the activation efficiency of T-705 and T-1105 in four cell lines that are commonly used for their antiviral evaluation. In MDCK cells, the levels of T-705-RTP were markedly lower than those of T-1105-RTP, while the opposite was seen in A549, Vero and HEK293T cells. In the latter three cell lines, T-1105 activation was hindered by inefficient conversion of the ribonucleoside monophosphate to the ribonucleoside diphosphate en route to forming the active triphosphate. Accordingly, T-1105 had better anti-RNA virus activity in MDCK cells, while T-705 was more potent in the other three cell lines. Additionally, we identified a fourth metabolite, the NAD analogue of T-705/T-1105, and showed that it can be formed by nicotinamide mononucleotide adenylyltransferase.
抗病毒药物 T-705（法匹拉韦）及其无氟类似物 T-1105 在转化为核糖核苷三磷酸（RTP）代谢物后，可抑制 RNA 病毒的聚合酶。我们在此比较了 T-705 和 T-1105 在四种常用于抗病毒评估的常见细胞系中的激活效率。在 MDCK 细胞中，T-705-RTP 的水平明显低于 T-1105-RTP，而在 A549、Vero 和 HEK293T 细胞中则相反。在后三种细胞系中，T-1105 的激活受到核糖核苷酸单磷酸向核糖核苷酸二磷酸转化效率低下的阻碍，从而形成活性三磷酸。因此，T-1105 在 MDCK 细胞中具有更好的抗 RNA 病毒活性，而 T-705 在其他三种细胞系中更有效。此外，我们还鉴定出 T-705/T-1105 的第四种代谢物，即 T-705/T-1105 的烟酰胺单核苷酸腺嘌呤二核苷酸，表明它可以由烟酰胺单核苷酸腺嘌呤二核苷酸转酰胺酶形成。
