Phosphoproteome-Entailed Kinase-Substrate Landscape of Human-DENV-2 Interaction

Area of Science:

• Virology
• Molecular Biology
• Drug Discovery

Background:

• Dengue virus (DENV) causes significant global health issues, with no specific antiviral treatments available.
• DENV pathogenesis is linked to host kinase-driven phosphorylation pathways.
• Dengue virus type 2 (DENV-2) is the most virulent serotype.

Purpose of the Study:

• To identify host kinases that phosphorylate DENV proteins.
• To explore host-directed therapeutic strategies targeting these kinases for DENV-2 infection.

Main Methods:

• Utilized a kinase-substrate phosphomotif approach to predict phosphorylation sites on the DENV proteome.
• Integrated predicted interactions with DENV-2 phosphoproteome, protein-protein interaction data, and experimental viral phosphosites.
• Employed molecular docking and conservation analyses to validate kinase-substrate interactions and therapeutic relevance.

Main Results:

• Identified 359 potential human kinases phosphorylating DENV-2 proteins, with CDK9 as a central hub.
• Confirmed stable interactions between host kinases (CDK9, EEF2K, HASPIN, TNNI3K) and viral proteins (capsid, NS5).
• Demonstrated evolutionary conservation of predicted phosphorylation sites across DENV-2 strains.

Conclusions:

• Host kinases are critical regulators of DENV infection, representing potential therapeutic targets.
• Inhibiting identified host kinases impacts DENV-2 infection, supporting their therapeutic relevance.
• This research provides a foundation for developing host-directed therapies against dengue virus.