Structure-activity relationship study of peptidomimetic aldehydes as enterovirus 71 3C protease inhibitors

Eur J Med Chem. 2016 Nov 29:124:559-573. doi: 10.1016/j.ejmech.2016.08.064. Epub 2016 Aug 28.

Abstract

A series of peptidomimetic aldehydes were designed, synthesized, and evaluated for their biochemical activity against 3C protease (3Cpro) and anti-enterovirus 71 (EV71) activity in vitro. Molecular docking revealed that 5s (IC50 = 0.22 ± 0.07 μM, EC50 = 0.18 ± 0.05 μM) could bind well to the active site of EV71 3Cpro, which was consistent with the biological data compared to reference 5a (IC50 = 0.54 ± 0.02 μM, EC50 = 0.26 ± 0.07 μM). Structure and relationship study led to the discovery of aldehyde 5x (IC50 = 0.10 ± 0.02 μM, EC50 = 0.11 ± 0.07 μM), which exhibited the most potent 3Cpro inhibitory and antiviral activity.

Keywords: Biological activity; Enterovirus 71 (EV71); Peptidomimetic aldehydes; Structure–activity relationship (SAR) study.

MeSH terms

  • Aldehydes / pharmacology*
  • Enterovirus A, Human / drug effects
  • Enterovirus A, Human / enzymology*
  • Enzyme Activation / drug effects
  • HEK293 Cells
  • Humans
  • Inhibitory Concentration 50
  • Molecular Docking Simulation
  • Peptidomimetics* / pharmacology
  • Protease Inhibitors / chemical synthesis
  • Protease Inhibitors / chemistry*
  • Protease Inhibitors / pharmacology*
  • Structure-Activity Relationship

Substances

  • Aldehydes
  • Peptidomimetics
  • Protease Inhibitors