How small-molecule inhibitors of dengue-virus infection interfere with viral membrane fusion
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
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.
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.
Metrics
-
- 2,821
- views
-
- 518
- downloads
-
- 23
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.