Abstract
Binary pore-forming bacterial protein toxins, including anthrax, are among Nature's most potent biological weapons. Bacillus anthracis, the causative agent of anthrax, secretes three polypeptides: protective antigen (PA), lethal factor (LF), and edema factor (EF), which interact at the surface of mammalian cells to form toxic complexes. LF and EF are enzymes that target substrates within the cytosol; PA provides a heptameric pore to facilitate LF and EF transport into the cytosol. In the present study, we evaluate a series of positively charged poly(amido amine) (PAMAM) dendrimers with the goal of identifying potent inhibitors of anthrax toxin. We show that all tested cationic dendrimers block PA63 channels. However, size of the dendrimers increases with the generation number, which limits ability of the large multi-charged dendrimer to enter the channels. We identify optimal size and charge characteristics of the blockers testing the G0 - G8 generations of PAMAM dendrimers against the single PA63 using the high-resolution single-channel measurements in planar bilayer membranes. Besides, we investigate the kinetics of the PAMAM dendrimers - pore binding/dissociation reactions at different voltages and salt concentrations.View Large Image | View Hi-Res Image | Download PowerPoint Slide
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