title: Cross-inhibition between furin and lethal factor inhibitors.
abstract: Bacillus anthracis synthesizes two toxins composed of the three proteins: protective antigen (PA), lethal factor (LF), and edema factor (EF). The cleavage of PA on the cell surface by the convertase furin leads to the translocation of LF and EF into the cytosol. We have investigated the cross-inhibitory activities of the furin inhibitors hexa-d-arginine amide (D6R) and nona-d-arginine amide (D9R), which block the proteolytic activation of PA; and of the LF inhibitor In-2-LF, a peptide hydroxamate. D6R and D9R inhibit LF with IC(50s) of 300 and 10microM, respectively; conversely, In-2-LF also inhibits furin (IC(50) 2microM). In-2-LF was efficiently cleaved by furin with the concomitant loss of inhibitory activity on both LF and furin. Incubation of In-2-LF with LF however generated a product that retained partial inhibitory activity against LF. Combined treatment of cells with D6R and In-2-LF enhanced protection against anthrax lethal toxin, indicating that combined administration of inhibitors could represent an effective therapeutic approach.
authors.affiliation: Department of Biochemistry and Molecular Biology, Louisiana State University Health Sciences Center, 1901 Perdido St., New Orleans, LA 70112, USA.
authors.forename: Juan R
authors.initials: JR
authors.lastname: Peinado
authors.forename: Magdalena M
authors.initials: MM
authors.lastname: Kacprzak
authors.forename: Stephen H
authors.initials: SH
authors.lastname: Leppla
authors.forename: Iris
authors.initials: I
authors.lastname: Lindberg
mesh_terms: D000577:Amides / Q000737:chemistry; D000818:Animals; D000881:Anthrax / Q000188:drug therapy; D000942:Antigens, Bacterial / Q000378:metabolism; D001120:Arginine / Q000031:analogs & derivatives; D001408:Bacillus anthracis / Q000378:metabolism*; D001427:Bacterial Toxins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016466:CHO Cells; D006224:Cricetinae; D004791:Enzyme Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D045683:Furin / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006877:Hydroxamic Acids / Q000494:pharmacology; D051379:Mice; D009842:Oligopeptides / Q000494:pharmacology; D010455:Peptides / Q000494:pharmacology
chemical_list: D000577:Amides; D000942:Antigens, Bacterial; D001427:Bacterial Toxins; D004791:Enzyme Inhibitors; D006877:Hydroxamic Acids; D009842:Oligopeptides; D010455:Peptides; C492740:anthrax LF protease inhibitor; C030325:anthrax toxin; C492739:hexaarginine amide; C491427:nonaarginine; D001120:Arginine; D045683:Furin