2. Academic Validation
  3. Molecular Mechanism Underlying the Action of Influenza A Virus Fusion Inhibitor MBX2546

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

  • ACS Infect Dis. 2017 May 12;3(5):330-335. doi: 10.1021/acsinfecdis.6b00194.
Arnab Basu 1,  Gloria Komazin-Meredith 1,  Courtney McCarthy 1,  Aleksandar Antanasijevic 2,  Steven C Cardinale 1,  Rama K Mishra 3,  Dale L Barnard 4,  Michael Caffrey 2,  Lijun Rong 5,  Terry L Bowlin 1
Affiliations

Affiliations

  • 1 Microbiotix Inc., One Innovation Drive, Worcester, Massachusetts 01605, United States.
  • 2 Department of Biochemistry and Molecular Genetics, University of Illinois at Chicago , Chicago, Illinois 60607, United States.
  • 3 Center for Molecular Innovation and Drug Discovery, Northwestern University , Evanston, Illinois 60208, United States.
  • 4 Institute for Antiviral Research, Utah State University , Logan, Utah 84322, United States.
  • 5 Department of Microbiology and Immunology, College of Medicine, University of Illinois at Chicago , Chicago, Illinois 60612, United States.
PMID: 28301927 DOI: 10.1021/acsinfecdis.6b00194
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.

Keywords

endosome; fusion; hemagglutinin; influenza A virus; inhibitor; virus entry.

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