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Elife. 2018 Jul 12;7. pii: e36461. doi: 10.7554/eLife.36461.

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

Author information

1
Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, United States.
2
Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, United States.
3
Department of Microbiology and Immunobiology, Harvard Medical School, Boston, United States.
4
Howard Hughes Medical Institute, Harvard Medical School, Boston, 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.

KEYWORDS:

flavivirus; inhibitor mechanism; molecular biophysics; structural biology; virus; virus entry

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