Identification of a PA-binding peptide with inhibitory activity against influenza A and B virus replication.

2.50
Hdl Handle:
http://hdl.handle.net/10033/620831
Title:
Identification of a PA-binding peptide with inhibitory activity against influenza A and B virus replication.
Authors:
Wunderlich, Kerstin; Mayer, Daniel; Ranadheera, Charlene; Holler, Anne-Sophie; Mänz, Benjamin; Martin, Arnold; Chase, Geoffrey; Tegge, Werner; Frank, Ronald ( 0000-0003-2683-6511 ) ; Kessler, Ulrich; Schwemmle, Martin
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 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.
Affiliation:
Helmholtz Centre for infection research, Inhoffenstr. 7, 38124 Braunschweig, Germany.
Citation:
Identification of a PA-binding peptide with inhibitory activity against influenza A and B virus replication. 2009, 4 (10):e7517 PLoS ONE
Journal:
PloS one
Issue Date:
20-Oct-2009
URI:
http://hdl.handle.net/10033/620831
DOI:
10.1371/journal.pone.0007517
PubMed ID:
19841738
Type:
Article
Language:
en
ISSN:
1932-6203
Appears in Collections:
Publications of the research group Chemical Biology (CBIO)

Full metadata record

DC FieldValue Language
dc.contributor.authorWunderlich, Kerstinen
dc.contributor.authorMayer, Danielen
dc.contributor.authorRanadheera, Charleneen
dc.contributor.authorHoller, Anne-Sophieen
dc.contributor.authorMänz, Benjaminen
dc.contributor.authorMartin, Arnolden
dc.contributor.authorChase, Geoffreyen
dc.contributor.authorTegge, Werneren
dc.contributor.authorFrank, Ronalden
dc.contributor.authorKessler, Ulrichen
dc.contributor.authorSchwemmle, Martinen
dc.date.accessioned2017-02-20T10:27:37Z-
dc.date.available2017-02-20T10:27:37Z-
dc.date.issued2009-10-20-
dc.identifier.citationIdentification of a PA-binding peptide with inhibitory activity against influenza A and B virus replication. 2009, 4 (10):e7517 PLoS ONEen
dc.identifier.issn1932-6203-
dc.identifier.pmid19841738-
dc.identifier.doi10.1371/journal.pone.0007517-
dc.identifier.urihttp://hdl.handle.net/10033/620831-
dc.description.abstractThere 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.en
dc.language.isoenen
dc.rights.urihttp://creativecommons.org/licenses/by-nc-sa/4.0/*
dc.subject.meshAmino Acid Sequenceen
dc.subject.meshAnimalsen
dc.subject.meshAntiviral Agentsen
dc.subject.meshCell Lineen
dc.subject.meshChemistry, Pharmaceuticalen
dc.subject.meshDNA-Directed RNA Polymerasesen
dc.subject.meshDogsen
dc.subject.meshDrug Designen
dc.subject.meshHumansen
dc.subject.meshInfluenza A virusen
dc.subject.meshInfluenza B virusen
dc.subject.meshMolecular Sequence Dataen
dc.subject.meshProtein Bindingen
dc.subject.meshProtein Structure, Tertiaryen
dc.subject.meshRNA Replicaseen
dc.subject.meshRecombinant Fusion Proteinsen
dc.subject.meshSequence Homology, Amino Aciden
dc.subject.meshVirus Replicationen
dc.titleIdentification of a PA-binding peptide with inhibitory activity against influenza A and B virus replication.en
dc.typeArticleen
dc.contributor.departmentHelmholtz Centre for infection research, Inhoffenstr. 7, 38124 Braunschweig, Germany.en
dc.identifier.journalPloS oneen

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