Identification of high-affinity PB1-derived peptides with enhanced affinity to the PA protein of influenza A virus polymerase.

2.50
Hdl Handle:
http://hdl.handle.net/10033/620746
Title:
Identification of high-affinity PB1-derived peptides with enhanced affinity to the PA protein of influenza A virus polymerase.
Authors:
Wunderlich, Kerstin; Juozapaitis, Mindaugas; Ranadheera, Charlene; Kessler, Ulrich; Martin, Arnold; Eisel, Jessica; Beutling, Ulrike; Frank, Ronald; Schwemmle, Martin
Abstract:
The influenza A virus polymerase complex, consisting of the subunits PB1, PB2, and PA, represents a promising target for the development of new antiviral drugs. We have previously demonstrated the feasibility of targeting the protein-protein interaction domain between PA and PB1 using peptides derived from the extreme N terminus of PB1 (amino acids [aa] 1 to 15), comprising the PA-binding domain of PB1. To increase the binding affinity of these peptides, we performed a systematic structure-affinity relationship analysis. Alanine and aspartic acid scans revealed that almost all amino acids in the core binding region (aa 5 to 11) are indispensable for PA binding. Using a library of immobilized peptides representing all possible single amino acid substitutions, we were able to identify amino acid positions outside the core PA-binding region (aa 1, 3, 12, 14, and 15) that are variable and can be replaced by affinity-enhancing residues. Surface plasmon resonance binding studies revealed that combination of several affinity-enhancing mutations led to an additive effect. Thus, the feasibility to enhance the PA-binding affinity presents an intriguing possibility to increase antiviral activity of the PB1-derived peptide and one step forward in the development of an antiviral drug against influenza A viruses.
Affiliation:
Helmholtz Centre for infection research, Inhoffenstr. 7, 38124 Braunschweig, Germany.
Citation:
Identification of high-affinity PB1-derived peptides with enhanced affinity to the PA protein of influenza A virus polymerase. 2011, 55 (2):696-702 Antimicrob. Agents Chemother.
Journal:
Antimicrobial agents and chemotherapy
Issue Date:
Feb-2011
URI:
http://hdl.handle.net/10033/620746
DOI:
10.1128/AAC.01419-10
PubMed ID:
21135188
Type:
Article
Language:
en
ISSN:
1098-6596
Appears in Collections:
Publications of the research group Chemical Biology (CBIO)

Full metadata record

DC FieldValue Language
dc.contributor.authorWunderlich, Kerstinen
dc.contributor.authorJuozapaitis, Mindaugasen
dc.contributor.authorRanadheera, Charleneen
dc.contributor.authorKessler, Ulrichen
dc.contributor.authorMartin, Arnolden
dc.contributor.authorEisel, Jessicaen
dc.contributor.authorBeutling, Ulrikeen
dc.contributor.authorFrank, Ronalden
dc.contributor.authorSchwemmle, Martinen
dc.date.accessioned2017-01-24T15:13:42Z-
dc.date.available2017-01-24T15:13:42Z-
dc.date.issued2011-02-
dc.identifier.citationIdentification of high-affinity PB1-derived peptides with enhanced affinity to the PA protein of influenza A virus polymerase. 2011, 55 (2):696-702 Antimicrob. Agents Chemother.en
dc.identifier.issn1098-6596-
dc.identifier.pmid21135188-
dc.identifier.doi10.1128/AAC.01419-10-
dc.identifier.urihttp://hdl.handle.net/10033/620746-
dc.description.abstractThe influenza A virus polymerase complex, consisting of the subunits PB1, PB2, and PA, represents a promising target for the development of new antiviral drugs. We have previously demonstrated the feasibility of targeting the protein-protein interaction domain between PA and PB1 using peptides derived from the extreme N terminus of PB1 (amino acids [aa] 1 to 15), comprising the PA-binding domain of PB1. To increase the binding affinity of these peptides, we performed a systematic structure-affinity relationship analysis. Alanine and aspartic acid scans revealed that almost all amino acids in the core binding region (aa 5 to 11) are indispensable for PA binding. Using a library of immobilized peptides representing all possible single amino acid substitutions, we were able to identify amino acid positions outside the core PA-binding region (aa 1, 3, 12, 14, and 15) that are variable and can be replaced by affinity-enhancing residues. Surface plasmon resonance binding studies revealed that combination of several affinity-enhancing mutations led to an additive effect. Thus, the feasibility to enhance the PA-binding affinity presents an intriguing possibility to increase antiviral activity of the PB1-derived peptide and one step forward in the development of an antiviral drug against influenza A viruses.en
dc.language.isoenen
dc.subject.meshAmino Acid Sequenceen
dc.subject.meshAmino Acid Substitutionen
dc.subject.meshCell Lineen
dc.subject.meshHumansen
dc.subject.meshInfluenza A virusen
dc.subject.meshMolecular Sequence Dataen
dc.subject.meshPeptidesen
dc.subject.meshProtein Bindingen
dc.subject.meshProtein Interaction Domains and Motifsen
dc.subject.meshRNA Replicaseen
dc.subject.meshStructure-Activity Relationshipen
dc.subject.meshViral Proteinsen
dc.titleIdentification of high-affinity PB1-derived peptides with enhanced affinity to the PA protein of influenza A virus polymerase.en
dc.typeArticleen
dc.contributor.departmentHelmholtz Centre for infection research, Inhoffenstr. 7, 38124 Braunschweig, Germany.en
dc.identifier.journalAntimicrobial agents and chemotherapyen

Related articles on PubMed

All Items in HZI are protected by copyright, with all rights reserved, unless otherwise indicated.