In this study, we present an integrative antiviral drug repurposing methodology, which combines a systems pharmacology-based network medicine platform that quantifies the interplay between the virus–host interactome and drug targets in the human PPI network. The basis for these experiments rests on the notions that (i) the proteins that functionally associate with viral infection (including HCoV) are localized in the corresponding subnetwork within the comprehensive human PPI network and (ii) proteins that serve as drug targets for a specific disease may also be suitable drug targets for potential antiviral infection owing to common PPIs and functional pathways elucidated by the human interactome (Fig. 1). We follow this analysis with bioinformatics validation of drug-induced gene signatures and HCoV-induced transcriptomics in human cell lines to inspect the postulated mechanism-of-action in a specific HCoV for which we propose repurposing (Fig. 1).
Fig. 1 Overall workflow of this study.
Our network-based methodology combines a systems pharmacology-based network medicine platform that quantifies the interplay between the virus–host interactome and drug targets in the human PPI network. a Human coronavirus (HCoV)-associated host proteins were collected from literatures and pooled to generate a pan-HCoV protein subnetwork. b Network proximity between drug targets and HCoV-associated proteins was calculated to screen for candidate repurposable drugs for HCoVs under the human protein interactome model. c, d Gene set enrichment analysis was utilized to validate the network-based prediction. e Top candidates were further prioritized for drug combinations using network-based method captured by the “Complementary Exposure” pattern: the targets of the drugs both hit the HCoV–host subnetwork, but target separate neighborhoods in the human interactome network. f Overall hypothesis of the network-based methodology: (i) the proteins that functionally associate with HCoVs are localized in the corresponding subnetwork within the comprehensive human interactome network; and (ii) proteins that serve as drug targets for a specific disease may also be suitable drug targets for potential antiviral infection owing to common protein–protein interactions elucidated by the human interactome.