Potent inhibitors of furin and furin-like proprotein convertases containing decarboxylated P1 arginine mimetics

J Med Chem. 2010 Feb 11;53(3):1067-75. doi: 10.1021/jm9012455.


Furin belongs to the family of proprotein convertases (PCs) and is involved in numerous normal physiological and pathogenic processes, such as viral propagation, bacterial toxin activation, cancer, and metastasis. Furin and related furin-like PCs cleave their substrates at characteristic multibasic consensus sequences, preferentially after an arginine residue. By incorporating decarboxylated arginine mimetics in the P1 position of substrate analogue peptidic inhibitors, we could identify highly potent furin inhibitors. The most potent compound, phenylacetyl-Arg-Val-Arg-4-amidinobenzylamide (15), inhibits furin with a K(i) value of 0.81 nM and has also comparable affinity to other PCs like PC1/3, PACE4, and PC5/6, whereas PC2 and PC7 or trypsin-like serine proteases were poorly affected. In fowl plague virus (influenza A, H7N1)-infected MDCK cells, inhibitor 15 inhibited proteolytic hemagglutinin cleavage and was able to reduce virus propagation in a long-term infection test. Molecular modeling revealed several key interactions of the 4-amidinobenzylamide residue in the S1 pocket of furin contributing to the excellent affinity of these inhibitors.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Arginine / chemistry*
  • Arginine / pharmacology
  • Biomimetic Materials / chemical synthesis
  • Biomimetic Materials / chemistry
  • Biomimetic Materials / pharmacology*
  • Cell Line
  • Dogs
  • Furin / antagonists & inhibitors*
  • Hemagglutinin Glycoproteins, Influenza Virus / chemistry*
  • Humans
  • Influenza A virus / pathogenicity
  • Kinetics
  • Models, Molecular
  • Orthomyxoviridae Infections / drug therapy
  • Proprotein Convertases / antagonists & inhibitors*
  • Serine Proteinase Inhibitors / chemical synthesis
  • Serine Proteinase Inhibitors / chemistry
  • Serine Proteinase Inhibitors / pharmacology*
  • Structure-Activity Relationship
  • Substrate Specificity
  • Virus Replication / drug effects


  • Hemagglutinin Glycoproteins, Influenza Virus
  • Serine Proteinase Inhibitors
  • hemagglutinin, avian influenza A virus
  • Arginine
  • Proprotein Convertases
  • Furin