Targeting glucose metabolism with dichloroacetate (DCA) reduces zika virus replication in brain cortical progenitors at different stages of maturation

Antiviral Res. 2024 Aug:228:105933. doi: 10.1016/j.antiviral.2024.105933. Epub 2024 Jun 6.

Abstract

The underlying threat of new Zika virus (ZIKV) outbreaks remains, as no vaccines or therapies have yet been developed. In vitro research has shown that glycolysis is a key factor to enable sustained ZIKV replication in neuroprogenitors. However, neither in vivo nor clinical investigation of glycolytic modulators as potential therapeutics for ZIKV-related fetal abnormalities has been conducted. Accordingly, we tested the therapeutic potential of metabolic modulators in relevant in vitro systems comprising two pools of neuroprogenitors (NPCs), which resemble early and late stages of pregnancy. Effective doses of metabolic modulators [3.0 μM] dimethyl fumarate (DMF), [3.2 mM] dichloroacetate (DCA), and [6.3 μM] VER-246608 were determined for these cells by their effect on lactate release, pyruvate dehydrogenase (PDH) activity and cell survival. The drugs were used in a 24h pre-treatment and kept throughout ZIKV infection of NPCs. Drug effects and ZIKV replication were assessed at 24- and 56-h post-infection. In early NPCs treated with DMF, DCA and VER-246608, there was a significant reduction in the extracellular release of ZIKV potentially by PDH-mediated increased mitochondrial oxidation of glucose. Out of the three drugs, only DCA was observed to reduce viral replication in late NPCs treated with DCA. Altogether, our findings suggest that reduction of anaerobic glycolysis could be of therapeutic potential against ZIKV-related fetal abnormalities and that clinical translation should consider the use of specific glycolytic modulators over different trimesters.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antiviral Agents / pharmacology
  • Cell Survival / drug effects
  • Cells, Cultured
  • Dichloroacetic Acid* / pharmacology
  • Glucose* / metabolism
  • Glycolysis / drug effects
  • Humans
  • Mitochondria / drug effects
  • Mitochondria / metabolism
  • Neural Stem Cells / drug effects
  • Neural Stem Cells / metabolism
  • Neural Stem Cells / virology
  • Virus Replication* / drug effects
  • Zika Virus Infection* / drug therapy
  • Zika Virus Infection* / virology
  • Zika Virus* / drug effects
  • Zika Virus* / physiology

Substances

  • Dichloroacetic Acid
  • Glucose
  • Antiviral Agents