Harnessing viral internal proteins to combat flu and beyond

This mini-review examines the strategy of combining viral protein sequence conservation with drug-binding potential to identify novel antiviral targets, focusing on internal proteins of influenza A and other RNA viruses. The importance of combating viral genetic variability and reducing the likelihood of resistance development is emphasised in the context of sequence redundancy in viral datasets. It covers recent structural and functional updates, as well as drug targeting efforts for three internal influenza A viral proteins: Basic Polymerase 2, Nuclear Export Protein, and Nucleoprotein. The review discusses new insights into protein interactions, potential inhibitors, and recent drug discovery efforts. Similar approaches beyond influenza including Hepatitis E, SARS-CoV-2, Dengue, and the HIV-1 virus are also covered briefly. • Combining viral protein conservation with drug-binding potential aids in identifying novel antiviral targets. • Measures to account for sequence redundancy and sequencing bias are outlined. • Paliperidone, a repurposed antipsychotic, inhibits specific influenza A strains by targeting PB2. • Compounds like HAA-09 and 7-51A show potent antiviral activity by targeting the conserved PB2 cap-binding domain. • Combining protein stability, sequence conservation, binding site prediction, and molecular docking improves inhibitor identification.