Elongated and Shortened Peptidomimetic Inhibitors of the Proprotein Convertase Furin

ChemMedChem. 2017 Apr 20;12(8):613-620. doi: 10.1002/cmdc.201700108. Epub 2017 Apr 4.


Novel elongated and shortened derivatives of the peptidomimetic furin inhibitor phenylacetyl-Arg-Val-Arg-4-amidinobenzylamide were synthesized. The most potent compounds, such as Nα (carbamidoyl)Arg-Arg-Val-Arg-4-amidinobenzylamide (Ki =6.2 pm), contain additional basic residues at the N terminus and inhibit furin in the low-picomolar range. Furthermore, to decrease the molecular weight of this inhibitor type, compounds that lack the P5 moiety were prepared. The best inhibitors of this series, 5-(guanidino)valeroyl-Val-Arg-4-amidinobenzylamide and its P3 tert-leucine analogue displayed Ki values of 2.50 and 1.26 nm, respectively. Selected inhibitors, together with our previously described 4-amidinobenzylamide derivatives as references, were tested in cell culture for their activity against furin-dependent infectious pathogens. The propagation of the alphaviruses Semliki Forest virus and chikungunya virus was strongly inhibited in the presence of selected derivatives. Moreover, a significant protective effect of the inhibitors against diphtheria toxin was observed. These results confirm that the inhibition of furin should be a promising approach for the short-term treatment of acute infectious diseases.

Keywords: Semliki Forest virus; alphaviruses; chikungunya virus; diphtheria toxin; furin; inhibitors.

MeSH terms

  • Animals
  • Antiviral Agents / chemical synthesis
  • Antiviral Agents / pharmacology
  • Benzamides / chemical synthesis
  • Benzamides / pharmacology*
  • Cell Line
  • Chikungunya virus / drug effects
  • Chlorocebus aethiops
  • Cricetinae
  • Diphtheria Toxin / metabolism
  • Furin / antagonists & inhibitors*
  • Furin / metabolism
  • Oligopeptides / chemical synthesis
  • Oligopeptides / pharmacology*
  • Peptidomimetics / chemical synthesis
  • Peptidomimetics / pharmacology*
  • Semliki forest virus / drug effects
  • Serine Proteinase Inhibitors / chemical synthesis
  • Serine Proteinase Inhibitors / pharmacology*


  • Antiviral Agents
  • Benzamides
  • Diphtheria Toxin
  • Oligopeptides
  • Peptidomimetics
  • Serine Proteinase Inhibitors
  • Furin