Identification of potent and compartment-selective small molecule furin inhibitors using cell-based assays

Biochem Pharmacol. 2015 Jul 15;96(2):107-18. doi: 10.1016/j.bcp.2015.05.008. Epub 2015 May 21.


The proprotein convertase furin is implicated in a variety of pathogenic processes such as bacterial toxin activation, viral propagation, and cancer. Several groups have identified non-peptide compounds with high inhibitory potency against furin in vitro, although their efficacy in various cell-based assays is largely unknown. In this study we show that certain guanidinylated 2,5-dideoxystreptamine derivatives exhibit interesting ex vivo properties. Compound 1b (1,1'-(4-((2,4-diguanidino-5-(4-guanidinophenoxy)cyclohexyl)oxy)-1,3-phenylene)diguanidine) is a potent and cell-permeable inhibitor of cellular furin, since it was able to retard tumor cell migration, block release of a Golgi reporter, and protect cells against Bacillus anthracis (anthrax) and Pseudomonas aeruginosa intoxication, with no evident cell toxicity. Other compounds based on the 2,5-dideoxystreptamine scaffold, such as compound 1g (1,1'-(4,6-bis(4-guanidinophenoxy)cyclohexane-1,3-diyl)diguanidine) also efficiently protected cells against anthrax, but displayed only moderate protection against Pseudomonas exotoxin A and did not inhibit cell migration, suggesting poor cell permeability. Certain bis-guanidinophenyl ether derivatives such as 2f (1,3-bis(2,4-diguanidinophenoxy) benzene) exhibited micromolar potency against furin in vitro, low cell toxicity, and highly efficient protection against anthrax toxin; this compound only slightly inhibited intracellular furin. Thus, compounds 1g and 2f both represent potent furin inhibitors at the cell surface with low intracellular inhibitory action, and these particular compounds might therefore be of preferred therapeutic interest in the treatment of certain bacterial and viral infections.

Keywords: Cell-based assays; Furin; Furin inhibitors; Proprotein convertases; Protease.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Anti-Bacterial Agents / chemical synthesis
  • Anti-Bacterial Agents / chemistry*
  • Anti-Bacterial Agents / pharmacology
  • Bacillus anthracis / metabolism
  • Bacterial Toxins / pharmacology
  • Cell Line
  • Cell Membrane / enzymology
  • Cell Movement / drug effects
  • Cell Survival / drug effects
  • Cricetulus
  • Furin / antagonists & inhibitors*
  • Guanidines / chemical synthesis
  • Guanidines / chemistry*
  • Guanidines / pharmacology
  • Hexosamines / chemical synthesis
  • Hexosamines / chemistry*
  • Hexosamines / pharmacology
  • Humans
  • Intracellular Space / enzymology
  • Mice
  • Models, Molecular
  • Pseudomonas aeruginosa / metabolism
  • Structure-Activity Relationship


  • 2,5-dideoxystreptamine
  • Anti-Bacterial Agents
  • Bacterial Toxins
  • Guanidines
  • Hexosamines
  • Furin