Department of Anatomy, Faculty of Veterinary Medicine, Kasetsart University, Bangkok, 10900, Thailand.
Department of Microbiology and Immunology, Faculty of Veterinary Medicine, Kasetsart University, Bangkok, 10900, Thailand.
Vet Res Commun. 2024 Feb;48(1):329-343. doi: 10.1007/s11259-023-10211-0. Epub 2023 Sep 11.
Foot-and-mouth disease virus (FMDV) is a highly contagious pathogen that poses a significant threat to the global livestock industry. However, specific antiviral treatments against FMDV are currently unavailable. This study aimed to evaluate the antiviral activity of anticancer drugs, including kinase and non-kinase inhibitors against FMDV replication in BHK-21 cells. Sorafenib, a multi-kinase inhibitor, demonstrated a significant dose-dependent reduction in FMDV replication. It exhibited a half maximal effective concentration (EC50) value of 2.46 µM at the pre-viral entry stage and 2.03 µM at the post-viral entry stage. Further intracellular assays revealed that sorafenib effectively decreased 3D activity with a half maximal inhibitory concentration (IC50) of 155 nM, while not affecting 3C function. The study indicates that sorafenib influences host protein pathways during FMDV infection, primarily by potentiating the c-RAF canonical pathway and AKT/PI3K pathway. Molecular docking analysis demonstrated specific binding of sorafenib to the active site of FMDV 3D, interacting with crucial catalytic residues, including D245, D338, S298, and N307. Additionally, sorafenib exhibited significant binding affinity to the active site motifs of cellular kinases, namely c-RAF, AKT, and PI3K, which play critical roles in the viral life cycle. The findings suggest that sorafenib holds promise as a therapeutic agent against FMDV infection. Its mechanism of action may involve inhibiting FMDV replication by reducing 3D activity and regulating cellular kinases. This study provides insights for the development of novel therapeutic strategies to combat FMDV infections.
口蹄疫病毒（FMDV）是一种高度传染性的病原体，对全球畜牧业构成重大威胁。然而，目前尚无针对 FMDV 的特定抗病毒治疗方法。本研究旨在评估包括激酶和非激酶抑制剂在内的抗癌药物对 FMDV 在 BHK-21 细胞中的复制的抗病毒活性。多激酶抑制剂索拉非尼对 FMDV 复制具有显著的剂量依赖性抑制作用。它在病毒进入前阶段的半数最大有效浓度（EC50）值为 2.46 μM，在病毒进入后阶段的 EC50 值为 2.03 μM。进一步的细胞内测定表明，索拉非尼有效地降低了 3D 活性，半数最大抑制浓度（IC50）为 155 nM，同时不影响 3C 功能。该研究表明，索拉非尼在 FMDV 感染过程中影响宿主蛋白途径，主要通过增强 c-RAF 经典途径和 AKT/PI3K 途径。分子对接分析表明，索拉非尼特异性结合 FMDV 3D 的活性部位，与关键的催化残基相互作用，包括 D245、D338、S298 和 N307。此外，索拉非尼还表现出对细胞激酶的活性部位基序（包括 c-RAF、AKT 和 PI3K）的显著结合亲和力，这些激酶在病毒生命周期中起着关键作用。这些发现表明，索拉非尼有望成为一种针对 FMDV 感染的治疗药物。其作用机制可能涉及通过降低 3D 活性和调节细胞激酶来抑制 FMDV 复制。本研究为开发针对 FMDV 感染的新型治疗策略提供了思路。
