Identification of a PA-Binding Peptide with Inhibitory Activity against Influenza A and B Virus Replication Export

@article{citeulike:6058547, 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.}, author = {Wunderlich, Kerstin and Mayer, Daniel and Ranadheera, Charlene and Holler, Anne-Sophie and M\"{a}nz, Benjamin and Martin, Arnold and Chase, Geoffrey and Tegge, Werner and Frank, Ronald and Kessler, Ulrich and Schwemmle, Martin}, citeulike-article-id = {6058547}, citeulike-linkout-0 = {http://dx.doi.org/10.1371/journal.pone.0007517}, day = {20}, doi = {10.1371/journal.pone.0007517}, journal = {PLoS ONE}, keywords = {influenza, inhibition, polymerase, replication}, month = {October}, number = {10}, pages = {e7517+}, posted-at = {2009-11-03 08:29:53}, priority = {2}, publisher = {Public Library of Science}, title = {Identification of a PA-Binding Peptide with Inhibitory Activity against Influenza A and B Virus Replication}, url = {http://dx.doi.org/10.1371/journal.pone.0007517}, volume = {4}, year = {2009} }

TY - JOUR ID - citeulike:6058547 L3 - citeulike-article-id:6058547 N2 - 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. IS - 10 JF - PLoS ONE TI - Identification of a PA-Binding Peptide with Inhibitory Activity against Influenza A and B Virus Replication PB - Public Library of Science VL - 4 SP - e7517 KW - influenza KW - inhibition KW - polymerase KW - replication AU - Wunderlich, Kerstin AU - Mayer, Daniel AU - Ranadheera, Charlene AU - Holler, Anne-Sophie AU - Mänz, Benjamin AU - Martin, Arnold AU - Chase, Geoffrey AU - Tegge, Werner AU - Frank, Ronald AU - Kessler, Ulrich AU - Schwemmle, Martin PY - 2009/10/20/ UR - http://dx.doi.org/10.1371/journal.pone.0007517 ER -