Molecular Mechanism Underlying the Action of Influenza A Virus Fusion Inhibitor MBX2546

Arnab Basu, Gloria Komazin-Meredith, Courtney McCarthy, Aleksandar Antanasijevic, Steven C. Cardinale, Rama K. Mishra, Dale L. Barnard, Michael Caffrey, Lijun Rong, Terry L. Bowlin

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5 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)330-335
Number of pages6
JournalACS Infectious Diseases
Volume3
Issue number5
DOIs
StatePublished - May 12 2017

All Science Journal Classification (ASJC) codes

  • Infectious Diseases

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    Basu, A., Komazin-Meredith, G., McCarthy, C., Antanasijevic, A., Cardinale, S. C., Mishra, R. K., Barnard, D. L., Caffrey, M., Rong, L., & Bowlin, T. L. (2017). Molecular Mechanism Underlying the Action of Influenza A Virus Fusion Inhibitor MBX2546. ACS Infectious Diseases, 3(5), 330-335. https://doi.org/10.1021/acsinfecdis.6b00194