How small-molecule inhibitors of dengue-virus infection interfere with viral membrane fusion
- Harvard Medical School, United States
- 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.
Article and author information
Author details
Stephen C Harrison
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
- Reinhard Jahn, Max Planck Institute for Biophysical Chemistry, Germany
Version history
- Received: March 9, 2018
- Accepted: July 10, 2018
- Accepted Manuscript published: July 12, 2018 (version 1)
- 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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How small-molecule inhibitors of dengue-virus infection interfere with viral membrane fusion
eLife 7:e36461.
https://doi.org/10.7554/eLife.36461
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