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

ELife
Luke H ChaoStephen C Harrison

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.

References

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May 22, 2003·Proceedings of the National Academy of Sciences of the United States of America·Yorgo ModisStephen C Harrison
Jan 23, 2004·Nature·Yorgo ModisStephen C Harrison
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Jun 26, 2018·Cell Chemical Biology·Melissanne de WispelaerePriscilla L Yang

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Citations

Apr 25, 2020·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Kowit HengphasatpornThanyada Rungrotmongkol
May 28, 2020·Proceedings of the National Academy of Sciences of the United States of America·Corleone S DelaverisCarolyn R Bertozzi
May 6, 2020·Nature Microbiology·Theodore C Pierson, Michael S Diamond
Sep 29, 2019·F1000Research·Michela Mazzon, Mark Marsh
Jun 20, 2020·Current Topics in Medicinal Chemistry·Anusuya ShanmugamM Michael Gromiha
Nov 18, 2020·ACS Infectious Diseases·Abraham ParkRobert J Rawle
Jul 2, 2021·Annual Review of Virology·Han-Yuan Liu, Priscilla L Yang

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Methods Mentioned

BETA
fluorescence microscopy
Fluorescence
dynamic light scattering
electron microscopy
column chromatography
fluorescence recovery after photobleaching
size-exclusion chromatography

Software Mentioned

3i
Slidebook
ImageJ
Matlab

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