Discovery and structural optimization of 3-O-β-chacotriosyl oleanane-type triterpenoids as potent entry inhibitors of SARS-CoV-2 virus infections

Eur J Med Chem. 2021 Apr 5:215:113242. doi: 10.1016/j.ejmech.2021.113242. Epub 2021 Feb 8.


Currently, SARS-CoV-2 virus is an emerging pathogen that has posed a serious threat to public health worldwide. However, no agents have been approved to treat SARS-CoV-2 infections to date, underscoring the great need for effective and practical therapies for SARS-CoV-2 outbreaks. We reported that a focused screen of OA saponins identified 3-O-β-chacotriosyl OA benzyl ester 2 as a novel small molecule inhibitor of SARS-CoV-2 virus entry, via binding to SARS-CoV-2 glycoprotein (S). We performed structure-activity relationship profiling of 2 and discovered C-17-COOH of OA was an important modification site that improved both inhibitor potency toward SARS-CoV-2 and selectivity index. Then optimization from hit to lead resulted in a potent fusion inhibitor 12f displaying strong inhibition against infectious SARS-CoV-2 with an IC50 value of 0.97 μM in vitro. Mechanism studies confirmed that inhibition of SARS-CoV-2 viral entry of 12f was mediated by the direct interaction with SARS-CoV-2 S2 subunit to block membrane fusion. These 3-O-β-chacotriosyl OA amide saponins are suitable for further optimization as SARS-CoV-2 entry inhibitors with the potential to be developed as therapeutic agents for the treatment of SARS-CoV-2 virus infections.

Keywords: 3-O-β-chacotriosyl saponins; SARS-CoV-2 entry inhibitors; Structure-activity relationships.

MeSH terms

  • Animals
  • Antiviral Agents / chemical synthesis
  • Antiviral Agents / metabolism
  • Antiviral Agents / pharmacology*
  • Chlorocebus aethiops
  • Drug Discovery
  • HEK293 Cells
  • Humans
  • Microbial Sensitivity Tests
  • Molecular Structure
  • Protein Binding
  • Protein Subunits / metabolism
  • SARS-CoV-2 / drug effects*
  • Saponins / chemical synthesis
  • Saponins / metabolism
  • Saponins / pharmacology*
  • Spike Glycoprotein, Coronavirus / metabolism
  • Structure-Activity Relationship
  • Triterpenes / chemical synthesis
  • Triterpenes / metabolism
  • Triterpenes / pharmacology*
  • Vero Cells
  • Virus Internalization / drug effects*


  • Antiviral Agents
  • Protein Subunits
  • Saponins
  • Spike Glycoprotein, Coronavirus
  • Triterpenes
  • spike protein, SARS-CoV-2