Elsevier

Antiviral Research

Volume 185, January 2021, 104971
Antiviral Research

Research paper
structural characterization of the interaction between the C-terminal domain of the influenza polymerase PA subunit and an optimized small peptide inhibitor

https://doi.org/10.1016/j.antiviral.2020.104971Get rights and content
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Highlights

  • A new assay was developed to screen the inhibitors of protein-protein interaction between influenza polymerase subunits.

  • A minimal PB1 peptide sequence with nanomolar binding affinity was identified.

  • The crystal structure of the minimal PB1 peptide with the C-terminal part of PA subunit was determined at 1.6 Å resolution.

Abstract

Influenza viruses can cause severe respiratory infections in humans, leading to nearly half a million deaths worldwide each year. Improved antiviral drugs are needed to address the threat of development of novel pandemic strains. Current therapeutic interventions target three key proteins in the viral life cycle: neuraminidase, the M2 channel and RNA-dependent-RNA polymerase. Protein-protein interactions between influenza polymerase subunits are potential new targets for drug development. Using a newly developed assay based on AlphaScreen technology, we screened a peptide panel for protein-protein interaction inhibitors to identify a minimal PB1 subunit-derived peptide that retains high inhibition potential and can be further modified. Here, we present an X-ray structure of the resulting decapeptide bound to the C-terminal domain of PA polymerase subunit from pandemic isolate A/California/07/2009 H1N1 at 1.6 Å resolution and discuss its implications for the design of specific, potent influenza polymerase inhibitors.

Keywords

Antiviral peptides
Influenza a polymerase
Protein-protein interaction
AlphaScreen

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