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ACS Infect Dis. 2017 Mar 16. doi: 10.1021/acsinfecdis.6b00194. [Epub ahead of print]
Molecular Mechanism Underlying the Action of the Influenza A Virus Fusion Inhibitor MBX2546.
Basu A, Komazin-Meredith G, McCarthy C, Antanasijevic A, Cardinale SC, Mishra RK, Barnard DL, Caffrey M, Rong L, Bowlin TL.
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 is required for inhibition of viral infection, and (ii) binding of HA by MBX2546 represses the low-pH-induced conformational change of 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.
PMID: 28301927 DOI: 10.1021/acsinfecdis.6b00194
Molecular Mechanism Underlying the Action of the Influenza A Virus Fusion Inhibitor MBX2546.
Basu A, Komazin-Meredith G, McCarthy C, Antanasijevic A, Cardinale SC, Mishra RK, Barnard DL, Caffrey M, Rong L, Bowlin TL.
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 is required for inhibition of viral infection, and (ii) binding of HA by MBX2546 represses the low-pH-induced conformational change of 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.
PMID: 28301927 DOI: 10.1021/acsinfecdis.6b00194