Inhibition of the protein-protein interaction in influenza polymerase PA-PB1 subunit interface
The multidisciplinary team led by Milan Kožíšek and Jan Konvalinka from IOCB Prague in collaboration with scientists from the Institute of Molecular Genetics of the CAS developed a new AlphaScreen assay to find short peptides acting as nanomolar inhibitors of polymerase PA-PB1 subunit interface. Importantly, this area is conserved within a broad range of the influenza A strains. The results published in Antiviral Research provide also X-ray structural information useful for novel structure-assisted drug design.
The results published in Antiviral Research provide also X-ray structural information useful for novel structure-assisted drug design.
X-ray structure of the influenza polymerase PA C-terminal domain and an optimized PB1-like inhibitor
The video captures X-ray structures of the PA C-terminal domain in a complex with an optimized PB1-like inhibitor (decapeptide). In contrast to regular PPIs, the present PA-PB1 subunit interface interaction involves only a dozen of amino acid residues of the PB1 peptide that are embedded in a deep hydrophobic pocket of the PA domain. This unique feature gives us the chance to mimic PB-1 in the interface with drugs and thus efficiently stop the assembly of the influenza RNA-polymerase.
Read the paper:
- Hejdánek, J.; Radilová, K.; Pachl, P.; Hodek, J.; Machara, A.; Weber, J.; Řezáčová, P.; Konvalinka, J.; Kožíšek, M., structural characterization of the interaction between the C-terminal domain of the influenza polymerase PA subunit and an optimized small peptide inhibitor. Antiviral Research 2021, 185, 104971. https://doi.org/10.1016/j.antiviral.2020.104971