Small Molecules Targeting the Flavivirus E Protein with Broad-Spectrum Activity and Antiviral Efficacy in Vivo

ACS Infect Dis. 2019 Mar 8;5(3):460-472. doi: 10.1021/acsinfecdis.8b00322. Epub 2019 Jan 14.

Abstract

Vaccines and antivirals to combat dengue, Zika, and other flavivirus pathogens present a major, unmet medical need. Vaccine development has been severely challenged by the antigenic diversity of these viruses and the propensity of non-neutralizing, cross-reactive antibodies to facilitate cellular infection and increase disease severity. As an alternative, direct-acting antivirals targeting the flavivirus envelope protein, E, have the potential to act via an analogous mode of action without the risk of antibody-dependent enhancement of infection and disease. We previously discovered that structurally diverse small molecule inhibitors of the dengue virus E protein exhibit varying levels of antiviral activity against other flaviviruses in cell culture. Here, we demonstrate that the broad-spectrum activity of several cyanohydrazones against dengue, Zika, and Japanese encephalitis viruses is due to specific inhibition of E-mediated membrane fusion during viral entry and provide proof of concept for pharmacological inhibition of E as an antiviral strategy in vivo.

Keywords: antiviral; dengue virus; envelope protein inhibitor; flavivirus; fusion inhibitor; viral entry inhibitor.

Publication types

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

MeSH terms

  • Animals
  • Antiviral Agents / administration & dosage*
  • Antiviral Agents / chemistry
  • Female
  • Flavivirus / drug effects*
  • Flavivirus / physiology
  • Flavivirus Infections / drug therapy*
  • Flavivirus Infections / virology
  • Humans
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Small Molecule Libraries / administration & dosage*
  • Small Molecule Libraries / chemistry
  • Viral Envelope Proteins / antagonists & inhibitors
  • Viral Envelope Proteins / genetics
  • Viral Envelope Proteins / metabolism*
  • Virus Internalization / drug effects
  • Virus Replication / drug effects

Substances

  • Antiviral Agents
  • Small Molecule Libraries
  • Viral Envelope Proteins