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.