title: A peptide derived from the C-terminus of PB1 inhibits influenza virus replication by interfering with viral polymerase assembly.
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.
authors.affiliation: Key Laboratory of Protein and Peptide Pharmaceutical, National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.
authors.forename: Chunfeng
authors.initials: C
authors.lastname: Li
authors.forename: Qi
authors.initials: Q
authors.lastname: Ba
authors.forename: Aiping
authors.initials: A
authors.lastname: Wu
authors.forename: Hong
authors.initials: H
authors.lastname: Zhang
authors.forename: Tao
authors.initials: T
authors.lastname: Deng
authors.forename: Taijiao
authors.initials: T
authors.lastname: Jiang
mesh_terms: D000998:Antiviral Agents / Q000737:chemistry* / Q000494:pharmacology; D017930:Genes, Reporter; D057809:HEK293 Cells; D006801:Humans; D053118:Influenza A Virus, H1N1 Subtype / Q000187:drug effects / Q000201:enzymology / Q000502:physiology; D049409:Luciferases, Firefly / Q000096:biosynthesis / Q000235:genetics; D010446:Peptide Fragments / Q000737:chemistry* / Q000494:pharmacology; D011485:Protein Binding; D025941:Protein Interaction Mapping; D055503:Protein Multimerization; D017434:Protein Structure, Tertiary; D012324:RNA-Dependent RNA Polymerase / Q000037:antagonists & inhibitors / Q000737:chemistry*; D014764:Viral Proteins / Q000737:chemistry*; D014779:Virus Replication
chemical_list: D000998:Antiviral Agents; C057027:PB2 protein, Influenzavirus A; D010446:Peptide Fragments; D014764:Viral Proteins; C077346:influenza virus polymerase basic protein 1; D049409:Luciferases, Firefly; D012324:RNA-Dependent RNA Polymerase