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Molecular Mechanism Underlying the Action of Influenza A Virus Fusion Inhibitor MBX2546
Arnab Basu1, Gloria Komazin-Meredith1, Courtney McCarthy1
1Microbiotix Inc., One Innovation Drive, Worcester, Massachusetts 01605, United States.
Abstract:
Influenza A virus envelop protein hemagglutinin (HA) plays important roles in viral entry. We previously have reported that MBX2546, a novel influenza A virus inhibitor, binds to HA and inhibits HA-mediated membrane fusion. In this report, we show that (i) both binding and stabilization of HA by MBX2546 are required for the inhibition of viral infection and (ii) the binding of HA by MBX2546 represses the low-pH-induced conformational change in the HA, which is a prerequisite for membrane fusion. Mutations in MBX2546-resistant influenza A/PR/8/34 (H1N1) viruses are mapped in the HA stem region near the amino terminus of HA2. Finally, we have modeled the binding site of MBX2546 using molecular dynamics and find that the resulting structure is in good agreement with our results. Together, these studies underscore the importance of the HA stem loop region as a potential target for therapeutic intervention.
Insights
MBX2546, an influenza A virus inhibitor, binds to hemagglutinin (HA) and stabilizes it, preventing viral entry. This action targets the HA stem region, highlighting its therapeutic potential.
Area of Science:
- Virology
- Molecular Biology
- Drug Discovery
Background:
- Influenza A virus hemagglutinin (HA) is crucial for viral entry into host cells.
- Previous studies identified MBX2546 as a novel inhibitor that binds to HA and inhibits membrane fusion.
Purpose of the Study:
- To elucidate the mechanism by which MBX2546 inhibits influenza A virus infection.
- To identify the specific region of HA targeted by MBX2546 and its role in viral entry.
Main Methods:
- Investigated the requirement of HA binding and stabilization by MBX2546 for antiviral activity.
- Analyzed low-pH-induced conformational changes in HA upon MBX2546 binding.
- Mapped mutations in MBX2546-resistant viruses.
- Utilized molecular dynamics to model the MBX2546 binding site on HA.
Main Results:
- Both binding and stabilization of HA by MBX2546 are essential for inhibiting viral infection.
- MBX2546 binding prevents the low-pH-induced conformational change necessary for membrane fusion.
- Mutations conferring resistance to MBX2546 were located in the HA stem region (HA2 N-terminus).
- Molecular modeling supported the experimental findings regarding the binding site.
Conclusions:
- The HA stem loop region is a critical target for MBX2546's antiviral activity.
- MBX2546 represents a promising therapeutic strategy by targeting a conserved region of influenza HA.
- Understanding HA-inhibitor interactions can guide the development of new antiviral drugs.
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