Thermodynamic and structural characterization of an optimized peptide-based inhibitor of the influenza polymerase PA-PB1 subunit interaction

Influenza virus causes severe respiratory infection in humans. Current antivirotics target three key proteins in the viral life cycle: neuraminidase, the M2 channel and the endonuclease domain of RNA-dependent-RNA poly-merase. Due to the development of novel pandemic strains, additional antiviral drugs targetting different viral proteins are still needed. The protein-protein interaction between polymerase subunits PA and PB1 is one such possible target. We recently identified a modified decapeptide derived from the N-terminus of the PB1 subunit with high affinity for the C-terminal part of the PA subunit. Here, we optimized its amino acid hotspots to maintain the inhibitory potency and greatly increase peptide solubility. This allowed thermodynamic charac-terization of peptide binding to PA. Solving the X-ray structure of the peptide-PA complex provided structural insights into the interaction. Additionally, we optimized intracellular delivery of the peptide using a bicyclic strategy that led to improved inhibition in cell-based assays.

Automated summary

This study identified a modified peptide that interacts with the polymerase subunit PA of influenza virus and optimized its amino acid hotspots to enhance inhibitory potency and peptide solubility. The X-ray structure of the peptide-PA complex provided insights into their interaction. Improved inhibition in cell-based assays was achieved by optimizing intracellular delivery of the peptide using a bicyclic strategy.