title: Selective and potent furin inhibitors protect cells from anthrax without significant toxicity.
abstract: 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.
authors.affiliation: Sanford-Burnham Medical Research Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, United States.
authors.forename: Albert G
authors.initials: AG
authors.lastname: Remacle
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Gawlik
authors.forename: Vladislav S
authors.initials: VS
authors.lastname: Golubkov
authors.forename: Gregory W
authors.initials: GW
authors.lastname: Cadwell
authors.forename: Robert C
authors.initials: RC
authors.lastname: Liddington
authors.forename: Piotr
authors.initials: P
authors.lastname: Cieplak
authors.forename: Sherri Z
authors.initials: SZ
authors.lastname: Millis
authors.forename: Roxane
authors.initials: R
authors.lastname: Desjardins
authors.forename: Sophie
authors.initials: S
authors.lastname: Routhier
authors.forename: Xue Wen
authors.initials: XW
authors.lastname: Yuan
authors.forename: Witold A
authors.initials: WA
authors.lastname: Neugebauer
authors.forename: Robert
authors.initials: R
authors.lastname: Day
authors.forename: Alex Y
authors.initials: AY
authors.lastname: Strongin
mesh_terms: 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
chemical_list: D022122:Anthrax Vaccines; D000942:Antigens, Bacterial; D001427:Bacterial Toxins; D010446:Peptide Fragments; C030325:anthrax toxin; D045683:Furin