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How small-molecule inhibitors of dengue-virus infection interfere with viral membrane fusion

Dengue virus (DV) is a compact, icosahedrally symmetric, enveloped particle, covered by 90 dimers of envelope protein (E), which mediates viral attachment and membrane fusion. Fusion requires a dimer-to-trimer transition and membrane engagement of hydrophobic ‘fusion loops’. We previously characteri...

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Autores principales: Chao, Luke H, Jang, Jaebong, Johnson, Adam, Nguyen, Anthony, Gray, Nathanael S, Yang, Priscilla L, Harrison, Stephen C
Formato: Online Artículo Texto
Lenguaje:English
Publicado: eLife Sciences Publications, Ltd 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6056230/
https://www.ncbi.nlm.nih.gov/pubmed/29999491
http://dx.doi.org/10.7554/eLife.36461
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author Chao, Luke H
Jang, Jaebong
Johnson, Adam
Nguyen, Anthony
Gray, Nathanael S
Yang, Priscilla L
Harrison, Stephen C
author_facet Chao, Luke H
Jang, Jaebong
Johnson, Adam
Nguyen, Anthony
Gray, Nathanael S
Yang, Priscilla L
Harrison, Stephen C
author_sort Chao, Luke H
collection PubMed
description Dengue virus (DV) is a compact, icosahedrally symmetric, enveloped particle, covered by 90 dimers of envelope protein (E), which mediates viral attachment and membrane fusion. Fusion requires a dimer-to-trimer transition and membrane engagement of hydrophobic ‘fusion loops’. We previously characterized the steps in membrane fusion for the related West Nile virus (WNV), using recombinant, WNV virus-like particles (VLPs) for single-particle experiments (Chao et al., 2014). Trimerization and membrane engagement are rate-limiting; fusion requires at least two adjacent trimers; availability of competent monomers within the contact zone between virus and target membrane creates a trimerization bottleneck. We now report an extension of that work to dengue VLPs, from all four serotypes, finding an essentially similar mechanism. Small-molecule inhibitors of dengue virus infection that target E block its fusion-inducing conformational change. We show that ~12–14 bound molecules per particle (~20–25% occupancy) completely prevent fusion, consistent with the proposed mechanism.
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spelling pubmed-60562302018-07-25 How small-molecule inhibitors of dengue-virus infection interfere with viral membrane fusion Chao, Luke H Jang, Jaebong Johnson, Adam Nguyen, Anthony Gray, Nathanael S Yang, Priscilla L Harrison, Stephen C eLife Structural Biology and Molecular Biophysics Dengue virus (DV) is a compact, icosahedrally symmetric, enveloped particle, covered by 90 dimers of envelope protein (E), which mediates viral attachment and membrane fusion. Fusion requires a dimer-to-trimer transition and membrane engagement of hydrophobic ‘fusion loops’. We previously characterized the steps in membrane fusion for the related West Nile virus (WNV), using recombinant, WNV virus-like particles (VLPs) for single-particle experiments (Chao et al., 2014). Trimerization and membrane engagement are rate-limiting; fusion requires at least two adjacent trimers; availability of competent monomers within the contact zone between virus and target membrane creates a trimerization bottleneck. We now report an extension of that work to dengue VLPs, from all four serotypes, finding an essentially similar mechanism. Small-molecule inhibitors of dengue virus infection that target E block its fusion-inducing conformational change. We show that ~12–14 bound molecules per particle (~20–25% occupancy) completely prevent fusion, consistent with the proposed mechanism. eLife Sciences Publications, Ltd 2018-07-12 /pmc/articles/PMC6056230/ /pubmed/29999491 http://dx.doi.org/10.7554/eLife.36461 Text en © 2018, Chao et al http://creativecommons.org/licenses/by/4.0/ http://creativecommons.org/licenses/by/4.0/This article is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use and redistribution provided that the original author and source are credited.
spellingShingle Structural Biology and Molecular Biophysics
Chao, Luke H
Jang, Jaebong
Johnson, Adam
Nguyen, Anthony
Gray, Nathanael S
Yang, Priscilla L
Harrison, Stephen C
How small-molecule inhibitors of dengue-virus infection interfere with viral membrane fusion
title How small-molecule inhibitors of dengue-virus infection interfere with viral membrane fusion
title_full How small-molecule inhibitors of dengue-virus infection interfere with viral membrane fusion
title_fullStr How small-molecule inhibitors of dengue-virus infection interfere with viral membrane fusion
title_full_unstemmed How small-molecule inhibitors of dengue-virus infection interfere with viral membrane fusion
title_short How small-molecule inhibitors of dengue-virus infection interfere with viral membrane fusion
title_sort how small-molecule inhibitors of dengue-virus infection interfere with viral membrane fusion
topic Structural Biology and Molecular Biophysics
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6056230/
https://www.ncbi.nlm.nih.gov/pubmed/29999491
http://dx.doi.org/10.7554/eLife.36461
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