Indirect anti-influenza targets
The inherent capacity of the influenza virus to mutate its components under strong selective pressure gives rise to new virus strains every year. This phenomenon disarms the power of vaccination and of antiviral drugs, necessitating the development of alternative treatment strategies. Researchers on the EU-funded ANTIFLU (Innovative anti-influenza drugs excluding viral escape) project proposed to target host cell factors that are necessary for virus survival and replication. This strategy might overcome the limitations observed with current approaches. ANTIFLU work was based on the data obtained previously by the consortium partners regarding indirect influenza virus targets. The main objectives were to develop druggable lead compounds such as small molecule ligands and inhibitory RNA molecules effective against influenza infection. The compounds had to be tested in vitro for cytotoxicity and efficacy in an influenza replication assay. Using computer software based on the 3D structure of the target proteins, researchers designed novel inhibitors. Among the additional objectives of the study was the evaluation of how these inhibitors impact the emergence of virus escape mutations. The kinase part of the project resulted in an exciting identification of CLK1 kinase as a leading potential target for anti-influenza drugs. In the non-kinase part of ANTIFLU, the vATPase was determined as a new potential target for the efficient treatment. In addition, two commercially available inhibitors against Exportin 1 (XPO1), known as eukaryotic protein that mediates the nuclear export, were tested as clinical candidates with promising results. With respect to the inhibitory RNA molecules, two vATPase-targeting RNAi induced knockdown of the target gene in the lung epithelium of mice upon intra-tracheal application. The ANTIFLU study demonstrated that influenza infection can be efficiently treated by targeting human cell factors implicated in the virus life cycle. The proposed targets and treatments present a promising alternative for viral strains resistant to existing anti-influenza drugs, and their applicability could be extended to other viral infections.
Keywords
Influenza, ANTIFLU, virus escape, CLK1, vATPase
