Tang Hao, Jiang Feng, Zhang Zhi, Yang Jiaojiao, Li Lu, Zhang Qingye
Hubei Key Laboratory of Agricultural Bioinformatics, College of Informatics, Huazhong Agricultural University, Shizishan Street 1, Wuhan, 430070 Hubei, China.
National Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Shizishan Street 1, Wuhan, 430070 Hubei, China.
Brief Bioinform. 2025 May 1;26(3). doi: 10.1093/bib/bbaf163.
Host-directed antivirals offer a promising strategy for addressing the challenge of viral resistance. Virus-host interactions often trigger stage-specific metabolic reprogramming in the host, and the causal links between these interactions and virus-induced metabolic changes provide valuable insights for identifying host targets. In this study, we present a workflow for repurposing host-directed antivirals using virus-induced protein networks. These networks capture the dynamic progression of viral infection by integrating host proteins directly interacting with the virus and enzymes associated with significantly altered metabolic fluxes, identified through dual-species genome-scale metabolic models. This approach reveals numerous hub nodes as potential host targets. As a case study, 50 approved drugs with potential anti-influenza virus A (IVA) activity were identified through eight stage-specific IVA-induced protein networks, each comprising 699-899 hub nodes. Lisinopril, saxagliptin, and gliclazide were further validated for anti-IVA efficacy in vitro through assays measuring the inhibition of cytopathic effects and viral titers in A549 cells infected with IVA PR8. This workflow paves the way for the rapid repurposing of host-directed antivirals.
宿主导向性抗病毒药物为应对病毒耐药性挑战提供了一种很有前景的策略。病毒与宿主的相互作用常常会触发宿主在特定阶段的代谢重编程，而这些相互作用与病毒诱导的代谢变化之间的因果联系为确定宿主靶点提供了宝贵的见解。在本研究中，我们提出了一种利用病毒诱导的蛋白质网络来重新利用宿主导向性抗病毒药物的工作流程。这些网络通过整合直接与病毒相互作用的宿主蛋白以及通过双物种基因组规模代谢模型鉴定出的与显著改变的代谢通量相关的酶，捕捉病毒感染的动态进展。这种方法揭示了众多作为潜在宿主靶点的枢纽节点。作为一个案例研究，通过八个特定阶段的甲型流感病毒（IVA）诱导的蛋白质网络鉴定出了50种具有潜在抗IVA活性的已批准药物，每个网络包含699 - 899个枢纽节点。通过测量感染IVA PR8的A549细胞中细胞病变效应的抑制和病毒滴度的实验，进一步在体外验证了赖诺普利、沙格列汀和格列齐特的抗IVA疗效。这种工作流程为宿主导向性抗病毒药物的快速重新利用铺平了道路。
