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Cross-inhibition between furin and lethal factor inhibitors
Juan R Peinado1, Magdalena M Kacprzak, Stephen H Leppla
1Department of Biochemistry and Molecular Biology, Louisiana State University Health Sciences Center, 1901 Perdido St., New Orleans, LA 70112, USA.
Biochemical and Biophysical Research Communications
|September 11, 2004
Summary
Researchers explored inhibitors for Bacillus anthracis toxins. Combining furin inhibitors (D6R, D9R) with a lethal factor (LF) inhibitor (In-2-LF) enhanced cell protection against anthrax lethal toxin.
Area of Science:
- Microbiology and Immunology
- Biochemistry and Molecular Biology
- Pharmacology and Toxicology
Background:
- Bacillus anthracis produces anthrax toxins, comprising protective antigen (PA), lethal factor (LF), and edema factor (EF).
- Proteolytic cleavage of PA by furin on cell surfaces facilitates LF and EF translocation into the host cell cytosol, mediating toxicity.
Purpose of the Study:
- To investigate the cross-inhibitory activities of furin inhibitors (hexa-d-arginine amide [D6R] and nona-d-arginine amide [D9R]) and a lethal factor inhibitor (In-2-LF).
- To evaluate the potential of combined inhibitor administration as a therapeutic strategy against anthrax lethal toxin.
Main Methods:
- Assessed the inhibitory concentrations (IC50s) of D6R, D9R, and In-2-LF against furin and LF.
- Examined the enzymatic cleavage of In-2-LF by furin and its effect on inhibitory activity.
- Investigated the interaction of In-2-LF with LF and the resulting product's activity.
- Evaluated the protective effects of combined D6R and In-2-LF treatment in cell-based assays.
Main Results:
- D6R and D9R demonstrated inhibitory activity against LF (IC50s of 300 and 10 μM, respectively).
- In-2-LF inhibited furin (IC50 of 2 μM) and was cleaved by furin, losing inhibitory activity against both targets.
- Incubation of In-2-LF with LF generated a product retaining partial LF inhibitory activity.
- Combined treatment with D6R and In-2-LF significantly enhanced cellular protection against anthrax lethal toxin.
Conclusions:
- Dual inhibition targeting both furin-mediated PA cleavage and LF activity offers enhanced protection against anthrax toxin.
- Combined administration of specific furin and LF inhibitors represents a promising therapeutic approach for anthrax.
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