Metabolism-associated protein network constructing and host-directed anti-influenza drug repurposing

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.