Biflavonoids from Torreya nucifera displaying SARS-CoV 3CL(pro) inhibition

Bioorg Med Chem. 2010 Nov 15;18(22):7940-7. doi: 10.1016/j.bmc.2010.09.035. Epub 2010 Sep 19.

Abstract

As part of our search for botanical sources of SARS-CoV 3CL(pro) inhibitors, we selected Torreya nucifera, which is traditionally used as a medicinal plant in Asia. The ethanol extract of T. nucifera leaves exhibited good SARS-CoV 3CL(pro) inhibitory activity (62% at 100μg/mL). Following bioactivity-guided fractionation, eight diterpenoids (1-8) and four biflavonoids (9-12) were isolated and evaluated for SARS-CoV 3CL(pro) inhibition using fluorescence resonance energy transfer analysis. Of these compounds, the biflavone amentoflavone (9) (IC(50)=8.3μM) showed most potent 3CL(pro) inhibitory effect. Three additional authentic flavones (apigenin, luteolin and quercetin) were tested to establish the basic structure-activity relationship of biflavones. Apigenin, luteolin, and quercetin inhibited 3CL(pro) activity with IC(50) values of 280.8, 20.2, and 23.8μM, respectively. Values of binding energy obtained in a molecular docking study supported the results of enzymatic assays. More potent activity appeared to be associated with the presence of an apigenin moiety at position C-3' of flavones, as biflavone had an effect on 3CL(pro) inhibitory activity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apigenin / chemistry
  • Apigenin / pharmacology
  • Biflavonoids / chemistry*
  • Biflavonoids / isolation & purification
  • Biflavonoids / pharmacology
  • Binding Sites
  • Catalytic Domain
  • Computer Simulation
  • Coronavirus 3C Proteases
  • Cysteine Endopeptidases / metabolism
  • Fluorescence Resonance Energy Transfer
  • Luteolin / chemistry
  • Luteolin / pharmacology
  • Plant Leaves / chemistry
  • Protease Inhibitors / chemistry*
  • Protease Inhibitors / isolation & purification
  • Protease Inhibitors / pharmacology
  • Quercetin / chemistry
  • Quercetin / pharmacology
  • SARS Virus / enzymology
  • Structure-Activity Relationship
  • Taxaceae / chemistry*
  • Viral Proteins / antagonists & inhibitors*
  • Viral Proteins / metabolism

Substances

  • Biflavonoids
  • Protease Inhibitors
  • Viral Proteins
  • Apigenin
  • amentoflavone
  • Quercetin
  • Cysteine Endopeptidases
  • Coronavirus 3C Proteases
  • Luteolin