Synergistic combination of orally available safe-in-man pleconaril, AG7404, and mindeudesivir inhibits enterovirus infections in human cell and organoid cultures

Cell Mol Life Sci. 2025 Jan 23;82(1):57. doi: 10.1007/s00018-025-05581-4.

Abstract

Enteroviruses can infect various human organs, causing diseases such as meningitis, the common cold, hand-foot-and-mouth disease, myocarditis, pancreatitis, hepatitis, poliomyelitis, sepsis, and type 1 diabetes. Currently, there are no approved treatments for enterovirus infections. In this study, we identified a synergistic combination of orally available, safe-in-man pleconaril, AG7404, and mindeudesivir, that at non-toxic concentrations effectively inhibited enterovirus replication in human cell and organoid cultures. Importantly, the cocktail did not alter glucose and insulin levels in the culture medium of pancreatic β-cells and preserved the contraction rhythm of infected heart organoids. These findings highlight a promising drug cocktail for further preclinical studies and clinical trials targeting a broad range of enterovirus-mediated diseases.

Keywords: Antiviral drug combination; Broad-spectrum antivirals; Drug synergy; Enterovirus.

MeSH terms

  • Administration, Oral
  • Antiviral Agents* / administration & dosage
  • Antiviral Agents* / pharmacology
  • Cells, Cultured
  • Drug Synergism*
  • Enterovirus / drug effects
  • Enterovirus / physiology
  • Enterovirus Infections* / drug therapy
  • Enterovirus Infections* / virology
  • Humans
  • Insulin-Secreting Cells / drug effects
  • Insulin-Secreting Cells / metabolism
  • Insulin-Secreting Cells / virology
  • Organoids* / drug effects
  • Organoids* / metabolism
  • Organoids* / virology
  • Oxadiazoles* / administration & dosage
  • Oxadiazoles* / chemistry
  • Oxadiazoles* / pharmacology
  • Oxazoles / pharmacology
  • Virus Replication* / drug effects

Substances

  • pleconaril
  • Antiviral Agents
  • Oxadiazoles
  • Oxazoles