Synthesis and Evolution of Berberine Derivatives as a New Class of Antiviral Agents against Enterovirus 71 through the MEK/ERK Pathway and Autophagy

Molecules. 2018 Aug 20;23(8):2084. doi: 10.3390/molecules23082084.

Abstract

Taking berberine (BBR) as the lead, 23 new BBR derivatives were synthesized and examined for their antiviral activities against four different genotype enterovirus 71 (EV71) strains with a cytopathic effect (CPE) assay. Structure-activity relationship (SAR) studies indicated that introduction of a suitable substituent at the 9-position might be beneficial for potency. Among them, compound 2d exhibited most potent activities with IC50 values of 7.12⁻14.8 μM, similar to that of BBR. The effect of 2d was further confirmed in a dose-dependent manner both in RNA and protein level. The mechanism revealed that 2d could inhibit the activation of MEK/ERK signaling pathway. Meanwhile, it could suppress the EV71-induced autophagy by activating AKT and inhibiting the phosphorylation of JNK and PI3KIII proteins. We consider BBR derivatives to be a new family of anti-EV71 agents through targeting host components, with an advantage of broad-spectrum anti-EV71 potency.

Keywords: MEK/ERK pathway; autophagy; berberine; enterovirus 71; structure-activity relationship.

MeSH terms

  • Antiviral Agents / chemical synthesis
  • Antiviral Agents / pharmacology*
  • Autophagy / drug effects*
  • Berberine / analogs & derivatives*
  • Berberine / chemical synthesis
  • Berberine / pharmacology*
  • Enterovirus A, Human / drug effects*
  • Humans
  • MAP Kinase Kinase 4 / antagonists & inhibitors
  • MAP Kinase Signaling System / drug effects*
  • Phosphorylation
  • Protein Kinase Inhibitors / chemical synthesis
  • Protein Kinase Inhibitors / pharmacology*
  • Structure-Activity Relationship
  • Virus Replication / drug effects

Substances

  • Antiviral Agents
  • Protein Kinase Inhibitors
  • Berberine
  • MAP Kinase Kinase 4