A peptide derived from the C-terminus of PB1 inhibits influenza virus replication by interfering with viral polymerase assembly

FEBS J. 2013 Feb;280(4):1139-49. doi: 10.1111/febs.12107. Epub 2013 Jan 31.

Abstract

Efficient assembly of the influenza virus RNA-dependent RNA polymerase, a heterotrimeric complex formed by three subunits (PA, PB1 and PB2) is critical for virus replication and pathogenicity. Therefore, interfering with the assembly of the RNA-dependent RNA polymerase complex could offer novel and effective anti-influenza therapeutics. In the present study, we show that a short peptide derived from amino acids 731-757 of PB1 (PB1(731-757)) can disrupt the interaction between the C-terminal part of PB1 (denoted as PB1c corresponding to PB1(676-757)) and the N-terminal part of PB2 (denoted as PB2n corresponding to PB2(1-40) ). We further show that PB1(731-757) is capable of inhibiting viral polymerase activity and viral replication. Interestingly, we find that PB1(731-757) interacts with PB1c rather than PB2n. Furthermore, mutational analyses show that the hydrophobic sites of PB1c play an essential role in the PB1c-PB1(731-757) interaction. The characterization of the inhibitory effect of PB1(731-757) on viral polymerase activity and viral replication could offer a potential target for anti-influenza drug development.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antiviral Agents / chemistry*
  • Antiviral Agents / pharmacology
  • Genes, Reporter
  • HEK293 Cells
  • Humans
  • Influenza A Virus, H1N1 Subtype / drug effects
  • Influenza A Virus, H1N1 Subtype / enzymology
  • Influenza A Virus, H1N1 Subtype / physiology
  • Luciferases, Firefly / biosynthesis
  • Luciferases, Firefly / genetics
  • Peptide Fragments / chemistry*
  • Peptide Fragments / pharmacology
  • Protein Binding
  • Protein Interaction Mapping
  • Protein Multimerization*
  • Protein Structure, Tertiary
  • RNA-Dependent RNA Polymerase / antagonists & inhibitors
  • RNA-Dependent RNA Polymerase / chemistry*
  • Viral Proteins / chemistry*
  • Virus Replication*

Substances

  • Antiviral Agents
  • PB2 protein, Influenzavirus A
  • Peptide Fragments
  • Viral Proteins
  • influenza virus polymerase basic protein 1
  • Luciferases, Firefly
  • RNA-Dependent RNA Polymerase