Background: Chikungunya virus (CHIKV) outbreaks have affected the global population and demand effective antiviral strategies. Exploring the molecular mechanisms associated with its pathogenesis through modulation of host response is essential for the development of efficient antiviral interventions. Although CHIKV-encoded kinases are not perceived, the phosphorylation of CHIKV proteins in hosts is reported. Hence, elucidating the signaling cross-talks between host kinases and viral proteins provides opportunities for targeted therapeutic strategies.

Methods: Toward this, we predicted the phosphosites in CHIKV proteins and their potential host kinases using multiple prediction tools, followed by a human kinase substrate phosphomotif pattern analysis to identify putative kinase interactions. The phosphoproteome of CHIKV and CHIKV-infected host cells and further the host-viral interactome were analyzed in conjunction with kinase inhibition assays to identify host kinases associated with their infection. Subsequently, in silico protein-protein docking was performed between the selected kinases and viral proteins to identify potential interactions.

Results and conclusion: In silico analysis revealed Mitogen-activated protein kinase 1 (MAPK1), Protein kinase C alpha (PRKCA), and Eukaryotic elongation factor 2 kinase (EEF2K) as major host kinases of specific phosphosites in CHIKV proteins. Putative kinases were also predicted for the reported phosphorylation sites in the CHIKV phosphoproteome. This study reveals that host kinases may phosphorylate substrates critical to CHIKV persistence and pathogenesis and emphasizes the potential of targeting host kinases as an adjunct to antiviral strategies. Our approach demonstrates the utility of kinase substrate specificity modeling to identify host kinases that can interact with viral proteins for their selection as drug-repurposable targets, particularly for variants and viruses without efficient/approved vaccines.