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

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

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antiviral Agents / chemical synthesis
  • Antiviral Agents / pharmacology*
  • Cell Membrane / metabolism
  • Dengue Virus / drug effects*
  • Dengue Virus / physiology*
  • Models, Biological
  • Protein Multimerization
  • Rhodamines / chemical synthesis
  • Rhodamines / pharmacology
  • Sulfonic Acids / chemical synthesis
  • Sulfonic Acids / pharmacology
  • Viral Envelope Proteins / metabolism
  • Virosomes / drug effects
  • Virus Internalization / drug effects*

Substances

  • Alexa Fluor 555
  • Antiviral Agents
  • Rhodamines
  • Sulfonic Acids
  • Viral Envelope Proteins
  • Virosomes