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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.

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


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.


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

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