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

0563164 - ÚOCHB 2023 RIV NL eng J - Článek v odborném periodiku
Radilová, Kateřina - Zima, Václav - Král, Michal - Machara, Aleš - Majer, Pavel - Hodek, Jan - Weber, Jan - Brynda, Jiří - Strmeň, Timotej - Konvalinka, Jan - Kožíšek, Milan
Thermodynamic and structural characterization of an optimized peptide-based inhibitor of the influenza polymerase PA-PB1 subunit interaction.
Antiviral Research. Roč. 208, December (2022), č. článku 105449. ISSN 0166-3542. E-ISSN 1872-9096
Grant CEP: GA MŠMT(CZ) EF16_019/0000729; GA MŠMT(CZ) LX22NPO5103
Institucionální podpora: RVO:61388963
Klíčová slova: antiviral peptides * influenza A polymerase * protein-protein interaction * AlphaScreen * isothermal titration calorimetry
Obor OECD: Biochemistry and molecular biology
Impakt faktor: 7.6, rok: 2022
Způsob publikování: Open access
https://doi.org/10.1016/j.antiviral.2022.105449

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 polymerase. 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 characterization 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.
Trvalý link: https://hdl.handle.net/11104/0335206