• Contact
• How to Find Us
• Organisations
• Media

Development of novel inhibitors of the influenza A virus polymerase

Abstract:

There is an urgent need for new drugs against influenza type A and B viruses due to incomplete protection by vaccines and the emergence of resistance to current antivirals. The influenza virus polymerase complex, consisting of the PB1, PB2 and PA subunits, represents a promising target for the development of new antivirals. We have previously demonstrated the feasibility of targeting the protein-protein interaction domain between the PB1 and PA subunits of the polymerase complex of influenza A (Ghanem et al. 2007) and B virus (Wunderlich et al, 2009) using a small peptide derived from the PA-binding domain of PB1. The goal of this project is to develop novel antiviral compounds that block the polymerase assembly of influenza A viruses.

This project is funded by the DFG and EC (FluCure)

Inhibition of the trimeric polymerase complex assembly. Correct assembly of the polymerase complex from the three viral polymerase subunits PB1, PB2 and PA is required for viral RNA synthesis of influenza viruses (A). Therefore, polymerase subunit interaction domains represent attractive targets for development of antivirals. We obtained proof of principle for influenza virus with a 25 amino acid peptide corresponding to the PA-binding domain of PB1 of influenza A virus (PB11-25). This peptide binds to PA (B) and was found to inhibit polymerase activity and replication of influenza viruses, most likely by interfering with the trimeric polymerase complex formation.

Investigators:

Mindaugas Juozapaitis
Peter Reuther

In collaboration with:

• Dr. Ulrich Kessler (PiKe Pharma, Zürich and member of the EC-project FluCure)

Selected References:

• Ghanem, A., Mayer, D., Chase, G., Tegge, W., Frank, R., Kochs, G., García-Stastre, A., Schwemmle, M.
  Peptide-mediated interference with influenza A virus polymerase
  J Virol 81: 7801-7804 (2007)
  >PubMed
• Wunderlich, K., Mayer, D., Ranadheera, C., Holler, A-S., Mänz, B., Martin, A., Chase, G., Tegge, W., Frank, R., Kessler, U., Schwemmle, M.
  Identification of a PA-Binding Peptide with Inhibitory Activity against Influenza A and B Virus Replication
  PLoS ONE 4: e7517 (2009)
  >PubMed
• Wunderlich, K., Juozapaitis, M., Mänz, B., Mayer, D., Götz, V., Zöhner, A., Wolff, T., Schwemmle, M., Martin, A.
  Limited Compatibility of Polymerase Subunit Interactions in Influenza A and B Viruses
  J Biol Chem 285: 16704-16712 (2010)
  >PubMed
• Wunderlich, K., Juozapaitis, M., Ranadheera, C., Kessler, U., Martin, A., Eisel, J., Beutling, U., Frank, R., Schwemmle, M.
  Identification of High-Affinity PB1-Derived Peptides with Enhanced Affinity to the PA Protein of Influenza A Virus Polymerase
  Antimicrob Agents Ch 55: 696-702 (2011)
  >PubMed
• Reuther, P., Mänz, B., Brunotte, L., Schwemmle, M., Wunderlich, K.
  Targeting of the Influenza A Virus Polymerase PB1-PB2 Interface Indicates Strain-Specific Assembly Differences
  J Virol 85: 13298-13309 (2011)
  >PubMed
• Chase, G., Wunderlich, K., Reuther, P., Schwemmle, M.
  Identification of influenza virus inhibitors which disrupt of viral polymerase protein-protein interactions
  Methods 55: 188-191 (2011)
  >PubMed

• deutsch