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

doi:10.1021/acsinfecdis.6b00194

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

^*Corresponding author for this work

Biochemistry and Molecular Genetics

Research output: Contribution to journal › Article › peer-review

18 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 language	English (US)
Pages (from-to)	330-335
Number of pages	6
Journal	ACS Infectious Diseases
Volume	3
Issue number	5
DOIs	https://doi.org/10.1021/acsinfecdis.6b00194
State	Published - May 12 2017

Keywords

endosome
fusion
hemagglutinin
influenza A virus
inhibitor
virus entry

ASJC Scopus subject areas

Infectious Diseases

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1021/acsinfecdis.6b00194

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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.",

keywords = "endosome, fusion, hemagglutinin, influenza A virus, inhibitor, virus entry",

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

note = "Publisher Copyright: {\textcopyright} 2017 American Chemical Society.",

year = "2017",

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day = "12",

doi = "10.1021/acsinfecdis.6b00194",

language = "English (US)",

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AU - Basu, Arnab

AU - Komazin-Meredith, Gloria

AU - McCarthy, Courtney

AU - Antanasijevic, Aleksandar

AU - Cardinale, Steven C.

AU - Mishra, Rama K.

AU - Barnard, Dale L.

AU - Caffrey, Michael

AU - Rong, Lijun

AU - Bowlin, Terry L.

PY - 2017/5/12

Y1 - 2017/5/12

N2 - 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.

AB - 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.

KW - endosome

KW - fusion

KW - hemagglutinin

KW - influenza A virus

KW - inhibitor

KW - virus entry

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

Abstract

Keywords

ASJC Scopus subject areas

UN SDGs

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