Department of Biological Science, University of Pittsburgh, Pittsburgh, PA 15260, USA.
Antiviral Res. 2012 Oct;96(1):70-81. doi: 10.1016/j.antiviral.2012.07.012. Epub 2012 Aug 7.
New polyomaviruses are continually being identified, and it is likely that links between this virus family and disease will continue to emerge. Unfortunately, a specific treatment for polyomavirus-associated disease is lacking. Because polyomaviruses express large Tumor Antigen, TAg, we hypothesized that small molecule inhibitors of the essential ATPase activity of TAg would inhibit viral replication. Using a new screening platform, we identified inhibitors of TAg's ATPase activity. Lead compounds were moved into a secondary assay, and ultimately two FDA approved compounds, bithionol and hexachlorophene, were identified as the most potent TAg inhibitors known to date. Both compounds inhibited Simian Virus 40 replication as assessed by plaque assay and quantitative PCR. Moreover, these compounds inhibited BK virus, which causes BKV Associated Nephropathy. In neither case was host cell viability compromised at these concentrations. Our data indicate that directed screening for TAg inhibitors is a viable method to identify polyomavirus inhibitors, and that bithionol and hexachlorophene represent lead compounds that may be further modified and/or ultimately used to combat diseases associated with polyomavirus infection.
新的多瘤病毒不断被发现，这种病毒家族与疾病之间的联系可能会继续出现。不幸的是，目前缺乏针对多瘤病毒相关疾病的特定治疗方法。由于多瘤病毒表达大的肿瘤抗原 TAg，我们假设 TAg 的必需 ATP 酶活性的小分子抑制剂将抑制病毒复制。使用新的筛选平台，我们鉴定了 TAg 的 ATP 酶活性抑制剂。先导化合物被转移到二次测定中，最终两种获得 FDA 批准的化合物，双羟萘酸和六氯酚，被鉴定为迄今为止已知最有效的 TAg 抑制剂。这两种化合物都抑制了猴病毒 40 的复制，如通过噬菌斑测定和定量 PCR 评估。此外，这两种化合物还抑制了 BK 病毒，后者可引起 BK 病毒相关肾病。在这些浓度下，宿主细胞活力均未受到损害。我们的数据表明，针对 TAg 抑制剂的定向筛选是一种可行的方法，可以鉴定多瘤病毒抑制剂，并且双羟萘酸和六氯酚代表可能进一步修饰和/或最终用于治疗与多瘤病毒感染相关疾病的先导化合物。
