Biochemistry, School of Natural Science and Centre for Chromosome Biology, NUI Galway, Galway, Ireland.
Institute of Organic Chemistry and Biochemistry, Czech Academy of Sciences, Prague, Czech Republic.
Antimicrob Agents Chemother. 2021 Feb 17;65(3). doi: 10.1128/AAC.01641-20.
Polyomavirus infections occur commonly in humans and are normally nonfatal. However, in immunocompromised individuals, they are intractable and frequently fatal. Due to a lack of approved drugs to treat polyomavirus infections, cidofovir, a phosphonate nucleotide analog approved to treat cytomegalovirus infections, has been repurposed as an antipolyomavirus agent. Cidofovir has been modified in various ways to improve its efficacies as a broad-spectrum antiviral agent. However, the actual mechanisms and targets of cidofovir and its modified derivatives as antipolyomavirus agents are still under research. Here, polyomavirus large tumor antigen (Tag) activities were identified as the viral target of cidofovir derivatives. The alkoxyalkyl ester derivatives of cidofovir efficiently inhibit polyomavirus DNA replication in cell-free human extracts and a viral replication system utilizing only purified proteins. We present evidence that DNA helicase and DNA binding activities of polyomavirus Tags are diminished in the presence of low concentrations of alkoxyalkyl ester derivatives of cidofovir, suggesting that the inhibition of viral DNA replication is at least in part mediated by inhibiting single-stranded DNA (ssDNA) and double-stranded DNA (dsDNA) binding activities of Tags. These findings show that the alkoxyalkyl ester derivatives of cidofovir are effective without undergoing further conversions, and we conclude that the inhibitory mechanisms of nucleotide analog-based drugs are more complex than previously believed.
多瘤病毒感染在人类中很常见，通常不会致命。然而，在免疫功能低下的个体中，它们是难以治疗的，并且经常是致命的。由于缺乏批准用于治疗多瘤病毒感染的药物，西多福韦，一种批准用于治疗巨细胞病毒感染的膦酸核苷酸类似物，已被重新用作抗多瘤病毒药物。西多福韦已通过各种方式进行修饰，以提高其作为广谱抗病毒药物的疗效。然而，西多福韦及其修饰衍生物作为抗多瘤病毒药物的实际机制和靶点仍在研究中。在这里，多瘤病毒大肿瘤抗原（Tag）的活性被确定为西多福韦衍生物的病毒靶标。西多福韦的烷氧基烷基酯衍生物在无细胞人提取物和仅使用纯化蛋白的病毒复制系统中有效地抑制多瘤病毒 DNA 复制。我们提供的证据表明，在低浓度的烷氧基烷基酯衍生物存在下，多瘤病毒 Tag 的 DNA 解旋酶和 DNA 结合活性降低，这表明病毒 DNA 复制的抑制至少部分是通过抑制 Tag 的单链 DNA（ssDNA）和双链 DNA（dsDNA）结合活性来介导的。这些发现表明，烷氧基烷基酯衍生物在未经进一步转化的情况下是有效的，我们得出结论，基于核苷酸类似物的药物的抑制机制比以前认为的要复杂。
