Identification of a PA-binding peptide with inhibitory activity against influenza A and B virus replication.
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 drugs. 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 virus using a small peptide derived from the PA-binding domain of PB1. However, this influenza A virus-derived peptide did not affect influenza B virus polymerase activity. Here we report that the PA-binding domain of the polymerase subunit PB1 of influenza A and B viruses is highly conserved and that mutual amino acid exchange shows that they cannot be functionally exchanged with each other. Based on phylogenetic analysis and a novel biochemical ELISA-based screening approach, we were able to identify an influenza A-derived peptide with a single influenza B-specific amino acid substitution which efficiently binds to PA of both virus types. This dual-binding peptide blocked the viral polymerase activity and growth of both virus types. Our findings provide proof of principle that protein-protein interaction inhibitors can be generated against influenza A and B viruses. Furthermore, this dual-binding peptide, combined with our novel screening method, is a promising platform to identify new antiviral lead compounds.
Department of Virology, University of Freiburg, Freiburg, Germany.
Kerstin
K
Wunderlich
Daniel
D
Mayer
Charlene
C
Ranadheera
Anne-Sophie
AS
Holler
Benjamin
B
Mänz
Arnold
A
Martin
Geoffrey
G
Chase
Werner
W
Tegge
Ronald
R
Frank
Ulrich
U
Kessler
Martin
M
Schwemmle
D000595:Amino Acid Sequence; D000818:Animals; D000998:Antiviral Agents / Q000737:chemistry / Q000494:pharmacology; D002460:Cell Line; D002626:Chemistry, Pharmaceutical / Q000379:methods; D012321:DNA-Directed RNA Polymerases / Q000737:chemistry*; D004285:Dogs; D015195:Drug Design; D006801:Humans; D009980:Influenza A virus / Q000378:metabolism*; D009981:Influenza B virus / Q000378:metabolism*; D008969:Molecular Sequence Data; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D012324:RNA-Dependent RNA Polymerase / Q000737:chemistry; D011993:Recombinant Fusion Proteins / Q000737:chemistry; D017386:Sequence Homology, Amino Acid; D014779:Virus Replication
D000998:Antiviral Agents; D011993:Recombinant Fusion Proteins; D012324:RNA-Dependent RNA Polymerase; D012321:DNA-Directed RNA Polymerases