title: Molecular Mechanism Underlying the Action of Influenza A Virus Fusion Inhibitor MBX2546.
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.
authors.affiliation: Microbiotix Inc., One Innovation Drive, Worcester, Massachusetts 01605, United States.
authors.forename: Arnab
authors.identifier: 0000-0001-5009-6985
authors.initials: A
authors.lastname: Basu
authors.affiliation: Microbiotix Inc., One Innovation Drive, Worcester, Massachusetts 01605, United States.
authors.forename: Gloria
authors.initials: G
authors.lastname: Komazin-Meredith
authors.affiliation: Microbiotix Inc., One Innovation Drive, Worcester, Massachusetts 01605, United States.
authors.forename: Courtney
authors.initials: C
authors.lastname: McCarthy
authors.affiliation: Department of Biochemistry and Molecular Genetics, University of Illinois at Chicago , Chicago, Illinois 60607, United States.
authors.forename: Aleksandar
authors.initials: A
authors.lastname: Antanasijevic
authors.affiliation: Microbiotix Inc., One Innovation Drive, Worcester, Massachusetts 01605, United States.
authors.forename: Steven C
authors.initials: SC
authors.lastname: Cardinale
authors.affiliation: Center for Molecular Innovation and Drug Discovery, Northwestern University , Evanston, Illinois 60208, United States.
authors.forename: Rama K
authors.initials: RK
authors.lastname: Mishra
authors.affiliation: Institute for Antiviral Research, Utah State University , Logan, Utah 84322, United States.
authors.forename: Dale L
authors.initials: DL
authors.lastname: Barnard
authors.affiliation: Department of Biochemistry and Molecular Genetics, University of Illinois at Chicago , Chicago, Illinois 60607, United States.
authors.forename: Michael
authors.initials: M
authors.lastname: Caffrey
authors.affiliation: Department of Microbiology and Immunology, College of Medicine, University of Illinois at Chicago , Chicago, Illinois 60612, United States.
authors.forename: Lijun
authors.initials: L
authors.lastname: Rong
authors.affiliation: Microbiotix Inc., One Innovation Drive, Worcester, Massachusetts 01605, United States.
authors.forename: Terry L
authors.initials: TL
authors.lastname: Bowlin
mesh_terms: D000083:Acetanilides / Q000737:chemistry*; D020816:Amino Acid Motifs; D000818:Animals; D000998:Antiviral Agents / Q000737:chemistry*; D001665:Binding Sites; D001681:Biological Assay; D004285:Dogs; D024882:Drug Resistance, Viral / Q000502:physiology; D019267:Hemagglutinin Glycoproteins, Influenza Virus / Q000737:chemistry* / Q000378:metabolism; D006863:Hydrogen-Ion Concentration; D053118:Influenza A Virus, H1N1 Subtype / Q000737:chemistry* / Q000187:drug effects / Q000378:metabolism; D007700:Kinetics; D061985:Madin Darby Canine Kidney Cells; D008561:Membrane Fusion / Q000187:drug effects*; D056004:Molecular Dynamics Simulation; D019906:Nuclear Magnetic Resonance, Biomolecular; D011485:Protein Binding; D000072756:Protein Conformation, alpha-Helical; D000072757:Protein Conformation, beta-Strand; D054730:Protein Interaction Domains and Motifs; D055503:Protein Multimerization; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism; D013449:Sulfonamides / Q000737:chemistry*
chemical_list: D000083:Acetanilides; D000998:Antiviral Agents; D019267:Hemagglutinin Glycoproteins, Influenza Virus; C000625208:MBX2546; D011994:Recombinant Proteins; D013449:Sulfonamides
keywords: endosome; fusion; hemagglutinin; influenza A virus; inhibitor; virus entry