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Identification of high-affinity PB1-derived peptides with enhanced affinity to the PA protein of influenza A virus polymerase.
Wunderlich, Kerstin Juozapaitis, Mindaugas Ranadheera, Charlene Kessler, Ulrich Martin, Arnold Eisel, Jessica Beutling, Ulrike Frank, Ronald Schwemmle, Martin
Wunderlich, Kerstin
Juozapaitis, Mindaugas
Ranadheera, Charlene
Kessler, Ulrich
Martin, Arnold
Eisel, Jessica
Beutling, Ulrike
Frank, Ronald
Schwemmle, Martin
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2011-02
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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.
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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.
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en
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1098-6596