National Engineering Research Center for the Emergency Drug, Beijing Institute of Pharmacology and Toxicology, Beijing 100850, P.R. China.
State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, School of Life Sciences, School of Public Health, Xiamen University, Xiamen 361102, P.R. China.
J Med Chem. 2022 Nov 10;65(21):14792-14808. doi: 10.1021/acs.jmedchem.2c01311. Epub 2022 Oct 17.
Enterovirus D68 (EV-D68) is a nonpolio enterovirus that is mainly transmitted through respiratory routes and poses a potential threat for large-scale spread. EV-D68 infections mostly cause moderate to severe respiratory diseases in children and potentially induce neurological diseases. However, there are no specific antiviral drugs or vaccines against EV-D68. Herein, through virtual screening and rational design, a series of novel quinoline analogues as anti-EV-D68 agents targeting VP1 were identified. Particularly, exhibited potent antiviral activity with an EC value ranging from 0.05 to 0.10 μM against various EV-D68 strains and showed inhibition of viral replication verified by Western blot, immunofluorescence, and plaque formation assay. Mechanistic studies indicated that the anti-EV-D68 agents work mainly by interacting with VP1. The acceptable bioavailability of 23.9% in rats and significant metabolic stability in human liver microsome (Cl = 10.8 mL/min/kg, = 148 min) indicated that compound with a novel scaffold was worth further investigation.
肠道病毒 D68（EV-D68）是一种主要通过呼吸道传播的非脊髓灰质炎肠道病毒，具有潜在的大规模传播威胁。EV-D68 感染主要在儿童中引起中度至重度呼吸道疾病，并可能诱发神经系统疾病。然而，目前尚无针对 EV-D68 的特异性抗病毒药物或疫苗。在此，我们通过虚拟筛选和合理设计，鉴定了一系列针对 VP1 的新型喹啉类似物作为抗 EV-D68 药物。特别是化合物 表现出针对各种 EV-D68 株的强大抗病毒活性，EC 值范围为 0.05 至 0.10 μM，并通过 Western blot、免疫荧光和蚀斑形成试验验证了其抑制病毒复制的能力。机制研究表明，这些抗 EV-D68 药物主要通过与 VP1 相互作用发挥作用。化合物 在大鼠中的生物利用度为 23.9%，在人肝微粒体中的代谢稳定性良好（Cl = 10.8 mL/min/kg，t1/2 = 148 min），表明具有新型骨架的化合物 值得进一步研究。
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