Characterization of a dengue NS4B inhibitor originating from an HCV small molecule library

Antiviral Res. 2017 Nov;147:149-158. doi: 10.1016/j.antiviral.2017.10.011. Epub 2017 Oct 14.

Abstract

Dengue is the most important mosquito-transmitted viral disease and a major global health concern. Over the last decade, dengue virus (DENV) drug discovery and development has intensified, however, this has not resulted in approved DENV-specific antiviral treatments yet. DENV and hepatitis C virus (HCV) belong to the same Flaviviridae family and, in contrast to DENV, antiviral treatments for HCV have been licensed. Therefore, applying the knowledge gained on anti-HCV drugs may foster the discovery and development of dengue antiviral drugs. Here, we screened a library of compounds with established anti-HCV activity in a DENV-2 sub-genomic replicon inhibition assay and selected compounds with single-digit micromolar activity. These compounds were advanced into a hit-to-lead medicinal chemistry program resulting in lead compound JNJ-1A, which inhibited the DENV-2 sub-genomic replicon at 0.7 μM, in the absence of cytotoxicity. In addition, JNJ-1A showed equipotent antiviral activity against DENV serotypes 1, 2, and 4. In vitro resistance selection experiments with JNJ-1A induced mutation T108I in non-structural protein 4B (NS4B), pointing towards a mechanism of action linked to this protein. Collectively, we described the discovery and characterization of a novel DENV inhibitor potentially targeting NS4B.

Keywords: Antiviral compound; Dengue; HCV; NS4B; Non-structural protein 4B.

MeSH terms

  • Animals
  • Antiviral Agents / chemistry
  • Antiviral Agents / pharmacokinetics
  • Antiviral Agents / pharmacology*
  • Antiviral Agents / toxicity
  • Cell Line, Tumor
  • Chlorocebus aethiops
  • Dengue
  • Dengue Virus / drug effects*
  • Dengue Virus / genetics
  • Dengue Virus / physiology
  • Drug Discovery
  • Drug Resistance, Viral / drug effects
  • Drug Resistance, Viral / genetics*
  • Hepacivirus / genetics
  • Humans
  • Mutation
  • RNA, Viral / genetics
  • Replicon / drug effects
  • Sequence Analysis, RNA
  • Small Molecule Libraries
  • Vero Cells
  • Viral Nonstructural Proteins / genetics*
  • Virus Replication / drug effects*

Substances

  • Antiviral Agents
  • RNA, Viral
  • Small Molecule Libraries
  • Viral Nonstructural Proteins