TY - JOUR
T1 - Identification of potent and compartment-selective small molecule furin inhibitors using cell-based assays
AU - Ramos-Molina, Bruno
AU - Lick, Adam N.
AU - Blanco, Elias H.
AU - Posada-Salgado, J. Alejandro
AU - Martinez-Mayorga, Karina
AU - Johnson, Alan T.
AU - Jiao, Guan Sheng
AU - Lindberg, Iris
N1 - Funding Information:
We thank Dr. A. Rehemtulla for providing us with the GRAPfurin cell system, and NIH grant R01 DA05084-27 for support. KMM thanks the Instituto de Quimica for financial support. We also thank John Giddens and Zephan Melville for performing preliminary studies of the Grap-furin and anthrax assays respectively.
Publisher Copyright:
© 2015 Elsevier Inc. All rights reserved.
PY - 2015/6/11
Y1 - 2015/6/11
N2 - 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.
AB - 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.
KW - Cell-based assays
KW - Furin
KW - Furin inhibitors
KW - Proprotein convertases
KW - Protease
UR - http://www.scopus.com/inward/record.url?scp=84930576034&partnerID=8YFLogxK
U2 - 10.1016/j.bcp.2015.05.008
DO - 10.1016/j.bcp.2015.05.008
M3 - Article
C2 - 26003844
AN - SCOPUS:84930576034
SN - 0006-2952
VL - 96
SP - 107
EP - 118
JO - Biochemical Pharmacology
JF - Biochemical Pharmacology
IS - 2
ER -