Selective and potent furin inhibitors protect cells from anthrax without significant toxicity.
Furin and related proprotein convertases cleave the multibasic motifs R-X-R/K/X-R in the precursor proteins and, as a result, transform the latent proproteins into biologically active proteins and peptides. Furin is present both in the intracellular secretory pathway and at the cell surface. Intracellular furin processes its multiple normal cellular targets in the Golgi and secretory vesicle compartments while cell-surface furin appears to be essential only for the processing of certain pathogenic proteins and, importantly, anthrax. To design potent, safe and selective inhibitors of furin, we evaluated the potency and selectivity of the derivatized peptidic inhibitors modeled from the extended furin cleavage sequence of avian influenza A H5N1. We determined that the N- and C-terminal modifications of the original RARRRKKRT inhibitory scaffold produced selective and potent, nanomolar range, inhibitors of furin. These inhibitors did not interfere with the normal cellular function of furin because of the likely functional redundancy existing between furin and other proprotein convertases. These furin inhibitors, however, were highly potent in blocking the furin-dependent cell-surface processing of anthrax protective antigen-83 both in vitro and cell-based assays and in vivo. We conclude that the inhibitors we have designed have a promising potential as selective anthrax inhibitors, without affecting major cell functions.
Remacle
Albert G
AG
Sanford-Burnham Medical Research Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, United States.
Gawlik
Katarzyna
K
Golubkov
Vladislav S
VS
Cadwell
Gregory W
GW
Liddington
Robert C
RC
Cieplak
Piotr
P
Millis
Sherri Z
SZ
Desjardins
Roxane
R
Routhier
Sophie
S
Yuan
Xue Wen
XW
Neugebauer
Witold A
WA
Day
Robert
R
Strongin
Alex Y
AY
D000818:Animals; D000881:Anthrax / Q000378:metabolism* / Q000517:prevention & control; D022122:Anthrax Vaccines; D000942:Antigens, Bacterial / Q000378:metabolism*; D001408:Bacillus anthracis / Q000502:physiology*; D001427:Bacterial Toxins / Q000378:metabolism*; D045744:Cell Line, Tumor; D003001:Cloning, Molecular; D019295:Computational Biology; D004330:Drosophila; D045683:Furin / Q000378:metabolism*; D006801:Humans; D010446:Peptide Fragments / Q000138:chemical synthesis / Q000378:metabolism*; D013379:Substrate Specificity
D022122:Anthrax Vaccines; D000942:Antigens, Bacterial; D001427:Bacterial Toxins; D010446:Peptide Fragments; C030325:anthrax toxin; D045683:Furin