Ding Rui, Edwards Tiffany C, Goswami Prithwish, Wilson Daniel J, Dreis Christine D, Ye Yihong, Geraghty Robert J, Chen Liqiang
Center for Drug Design, College of Pharmacy, University of Minnesota, Minneapolis, MN 55455, USA.
Laboratory of Molecular Biology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
Pharmaceuticals (Basel). 2025 Jan 19;18(1):131. doi: 10.3390/ph18010131.
p97 (also known as valosin-containing protein, VCP) is a member of the AAA+ ATPase family and is intimately associated with protein quality control and homeostasis regulation. Therefore, pharmaceutical inhibition of p97 has been actively pursued as an anticancer strategy. Recently, p97 has emerged as an important pro-viral host factor and p97 inhibitors are being evaluated as potential antiviral agents. We designed and synthesized novel p97 inhibitors based on the rearrangement of the central fused ring of our previously reported p97 inhibitors. These compounds were tested for inhibition of p97, cytotoxicity, and antiviral activity against SARS-CoV-2. Molecular docking was also performed on selected inhibitors to shed light on their binding modes. Among these new p97 inhibitors, two compounds possess enhanced anti-p97 activity over their parent compounds. More significantly, these two inhibitors exhibit strong antiviral activity against SARS-CoV-2 at doses with no significant cytotoxicity. Molecular docking reveals no major change of the binding mode relative to that of their parent compounds, further supporting our design strategy. These compounds are structurally novel p97 inhibitors that display low toxicity and possess promising antiviral activity against SARS-CoV-2 and potentially other viruses. Further structural exploration is therefore justified and improved analogs will serve as useful tools for studying p97 as a promising host antiviral target.
p97（也称为含缬酪肽蛋白，VCP）是AAA + ATP酶家族的成员，与蛋白质质量控制和稳态调节密切相关。因此，p97的药物抑制已被积极探索作为一种抗癌策略。最近，p97已成为一种重要的病毒前宿主因子，p97抑制剂正在被评估为潜在的抗病毒药物。我们基于之前报道的p97抑制剂的中心稠环重排设计并合成了新型p97抑制剂。测试了这些化合物对p97的抑制作用、细胞毒性以及对严重急性呼吸综合征冠状病毒2（SARS-CoV-2）的抗病毒活性。还对选定的抑制剂进行了分子对接，以阐明它们的结合模式。在这些新的p97抑制剂中，有两种化合物相对于其母体化合物具有增强的抗p97活性。更重要的是，这两种抑制剂在无明显细胞毒性的剂量下对SARS-CoV-2表现出强大的抗病毒活性。分子对接显示其结合模式相对于母体化合物没有重大变化，进一步支持了我们的设计策略。这些化合物是结构新颖的p97抑制剂，具有低毒性，对SARS-CoV-2以及潜在的其他病毒具有有前景的抗病毒活性。因此，进一步的结构探索是合理的，改进的类似物将成为研究p97作为有前景的宿主抗病毒靶点的有用工具。
