Related Experiment Videos
Characterization of a hemagglutinin-specific inhibitor of influenza A virus
1Department of Virology, Bristol-Myers Squibb Pharmaceutical Research Institute, Wallingford, Connecticut 06492, USA. Guangxiang_Luo@ccmail.bms.com
Abstract:
A novel inhibitor of influenza virus growth in tissue culture was identified and characterized. This compound (BMY-27709) has an IC50 of 3-8 microM for A/WSN/33 virus growth in a multicycle replication assay and is active against all H1 and H2 subtype viruses tested. However, BMY-27709 was found to be inactive against H3 subtype viruses, as well as influenza B/Lee/40 virus. BMY-27709 was also found to act against H1 and H2 viruses early in infection, suggesting that the target for inhibition is the hemagglutinin protein. This was confirmed through the use of reassortant viruses and the isolation of a virus resistant to BMY-27709. The resistant virus isolated contained a phenylalanine to serine change at amino acid 110 of the HA2 subunit. That this single mutation was responsible for the acquisition of resistance to BMY-27709 was proven through reverse genetics, as transfectant virus containing only this change was shown to be resistant to BMY-27709, while the control virus without this mutation remained sensitive. BMY-27709 is able to inhibit virus-induced red blood cell hemolysis, suggesting that it blocks the membrane fusion function of hemagglutinin. These experiments further illustrate that the hemagglutinin protein of influenza virus is a viable target for the discovery and development of small molecule inhibitors of virus growth.
Insights
A new compound, BMY-27709, effectively inhibits influenza A virus subtypes H1 and H2 by targeting the hemagglutinin protein. This discovery highlights hemagglutinin as a promising target for novel antiviral drug development.
Area of Science:
- Virology
- Drug Discovery
- Molecular Biology
Background:
- Influenza virus poses a significant global health threat, necessitating the development of new antiviral therapies.
- Current treatments are limited, and resistance can emerge.
- Identifying novel targets for antiviral intervention is crucial.
Purpose of the Study:
- To identify and characterize novel small molecule inhibitors of influenza virus replication.
- To determine the mechanism of action and target of the identified inhibitor.
- To evaluate the potential of the hemagglutinin protein as a target for antiviral drug development.
Main Methods:
- Screening for influenza virus inhibitors in tissue culture.
- Antiviral activity assays against various influenza virus subtypes (H1, H2, H3, and B).
- Mechanism of action studies using reassortant viruses, resistance selection, and reverse genetics.
- Hemolysis inhibition assays.
Main Results:
- A novel inhibitor, BMY-27709, was identified with potent activity against H1 and H2 influenza A viruses (IC50: 3-8 microM).
- BMY-27709 showed no activity against H3 influenza A viruses or influenza B virus.
- Resistance to BMY-27709 was mapped to a single amino acid mutation (Phe110Ser) in the HA2 subunit of hemagglutinin.
- BMY-27709 inhibited hemagglutinin-mediated membrane fusion and red blood cell hemolysis.
Conclusions:
- The hemagglutinin protein is a validated target for small molecule inhibitors of influenza virus.
- BMY-27709 represents a promising lead compound for the development of new influenza antivirals targeting hemagglutinin.
- Further research into hemagglutinin inhibitors could lead to effective treatments against influenza virus infections.