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

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.

SUBMITTER: Wunderlich K

PROVIDER: S-EPMC2759517 | biostudies-literature | 2009

REPOSITORIES: biostudies-literature

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

Wunderlich Kerstin K Mayer Daniel D Ranadheera Charlene C Holler Anne-Sophie AS Mänz Benjamin B Martin Arnold A Chase Geoffrey G Tegge Werner W Frank Ronald R Kessler Ulrich U Schwemmle Martin M

PloS one 20091020 10

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 ...[more]

PMID: 19841738

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Project description:Background:The influenza virus can cause seasonal infections with mild to severe symptoms, circulating worldwide, and it can affect people in any age group. Therefore, this infection is a serious public health problem that causes severe illness and death in high-risk populations. Every year, 0.5% of the world's population is infected by this pathogen. This percentage can increase up to ten times during pandemics. Influenza vaccination is the most effective way to prevent disease. In addition, anti-influenza drugs are essential for prophylactic and therapeutic interventions. The oseltamivir (OST, a neuraminidase inhibitor) is the primary antiviral used in clinics during outbreaks. However, OST resistant viruses may emerge naturally or due to antiviral pressure, with a prevalence of 1-2% worldwide. Thus, the search for new anti-influenza drugs is extremely important. Currently, several groups have been developing studies describing the biotechnological potential of microalgae and cyanobacteria, including antiviral activity of their extracts. In Brazil, this potential is poorly known and explored. Methods:With the aim of increasing the knowledge on this topic, 38 extracts from microalgae and cyanobacteria isolated from marine and freshwater biomes in Brazil were tested against: cellular toxicity; OST-sensitive and resistant influenza replications; and neuraminidase activity. Results:For this purpose, Madin-Darby Canine Kidney (MDCK)-infected cells were treated with 200 ?g/mL of each extract. A total of 17 extracts (45%) inhibited influenza A replication, with seven of them resulting in more than 80% inhibition. Moreover, functional assays performed with viral neuraminidase revealed two extracts (from Leptolyngbya sp. and Chlorellaceae) with IC50 mean < 210 ?g/mL for influenza A and B, and also OST-sensitive and resistant strains. Furthermore, MDCK cells exposed to 1 mg/mL of all the extracts showed viability higher than 80%. Discussion:Our results suggest that extracts of microalgae and cyanobacteria have promising anti-influenza properties. Further chemical investigation should be conducted to isolate the active compounds for the development of new anti-influenza drugs. The data generated contribute to the knowledge of the biotechnological potential of Brazilian biomes that are still little explored for this purpose.

Dataset Information

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

Publications

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

Similar Datasets

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