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Antimicrobial Agents and Chemotherapy, November 2006, p. 3740-3753, Vol. 50, No. 11
0066-4804/06/$08.00+0     doi:10.1128/AAC.00693-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Search for Cyclodextrin-Based Inhibitors of Anthrax Toxins: Synthesis, Structural Features, and Relative Activities

Innovative Biologics, Inc., 10900 University Blvd., Manassas, Virginia 20110,¹ Laboratory of Physical and Structural Biology, NICHD, National Institutes of Health, Bethesda, Maryland 20982,² Pinnacle Pharmaceuticals, Inc., Emerging Technology Center One, 1670 Discovery Dr., Charlottesville, Virginia 22911,³ Departments of Chemistry and Biology, University of Virginia, Charlottesville, Virginia 22901⁴

Received 5 June 2006/ Returned for modification 1 August 2006/ Accepted 27 August 2006

Recently, using structure-inspired drug design, we demonstrated that aminoalkyl derivatives of ß-cyclodextrin inhibited anthrax lethal toxin action by blocking the transmembrane pore formed by the protective antigen (PA) subunit of the toxin. In the present study, we evaluate a series of new ß-cyclodextrin derivatives with the goal of identifying potent inhibitors of anthrax toxins. Newly synthesized hepta-6-thioaminoalkyl and hepta-6-thioguanidinoalkyl derivatives of ß-cyclodextrin with alkyl spacers of various lengths were tested for the ability to inhibit cytotoxicity of lethal toxin in cells as well as to block ion conductance through PA channels reconstituted in planar bilayer lipid membranes. Most of the tested derivatives were protective against anthrax lethal toxin action at low or submicromolar concentrations. They also blocked ion conductance through PA channels at concentrations as low as 0.1 nM. The activities of the derivatives in both cell protection and channel blocking were found to depend on the length and chemical nature of the substituent groups. One of the compounds was also shown to block the edema toxin activity. It is hoped that these results will help to identify a new class of drugs for anthrax treatment, i.e., drugs that block the pathway for toxin translocation into the cytosol, the PA channel.

Published ahead of print on 18 September 2006.

This article has been cited by other articles:

• Moayeri, M., Robinson, T. M., Leppla, S. H., Karginov, V. A. (2008). In Vivo Efficacy of {beta}-Cyclodextrin Derivatives against Anthrax Lethal Toxin. Antimicrob. Agents Chemother. 52: 2239-2241 [Abstract] [Full Text]