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

  1. Luke H Chao
  2. Jaebong Jang
  3. Adam Johnson
  4. Anthony Nguyen
  5. Nathanael Gray
  6. Priscilla L Yang
  7. Stephen C Harrison  Is a corresponding author
  1. Harvard Medical School, United States
  2. Dana-Farber Cancer Institute, United States

Abstract

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.

Data availability

Simulation software deposited at Gihub.

The following data sets were generated

Article and author information

Author details

  1. Luke H Chao

    Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-4849-4148
  2. Jaebong Jang

    Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Adam Johnson

    Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Anthony Nguyen

    Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Nathanael Gray

    Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-5354-7403
  6. Priscilla L Yang

    Department of Microbiology and Immunobiology, Harvard Medical School, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-7456-2557
  7. Stephen C Harrison

    Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, United States
    For correspondence
    harrison@crystal.harvard.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-7215-9393

Funding

National Cancer Institute (CA13202)

  • Stephen C Harrison

National Institute of Allergy and Infectious Diseases (AI109740)

  • Stephen C Harrison

Howard Hughes Medical Institute

  • Stephen C Harrison

Charles A. King Trust

  • Luke H Chao

Jane Coffin Childs Memorial Fund for Medical Research

  • Luke H Chao

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Reinhard Jahn, Max Planck Institute for Biophysical Chemistry, Germany

Version history

  1. Received: March 9, 2018
  2. Accepted: July 10, 2018
  3. Accepted Manuscript published: July 12, 2018 (version 1)
  4. Version of Record published: July 23, 2018 (version 2)

Copyright

© 2018, Chao et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Luke H Chao
  2. Jaebong Jang
  3. Adam Johnson
  4. Anthony Nguyen
  5. Nathanael Gray
  6. Priscilla L Yang
  7. Stephen C Harrison
(2018)
How small-molecule inhibitors of dengue-virus infection interfere with viral membrane fusion
eLife 7:e36461.
https://doi.org/10.7554/eLife.36461

Share this article

https://doi.org/10.7554/eLife.36461

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