The results from our SBIR Phase II project demonstrated that ?-cyclodextrin derivatives designed to block the transmembrane channel formed by B. anthracis protective antigen can inhibit the cytotoxic effects of anthrax toxin at low- and sub-micromolar concentrations. Several compounds were tested in vivo and showed effective protection in rats challenged with lethal toxin and in mice infected with the spores of B. anthracis Sterne strain. The overall goal of this continuation project is to prove that the most promising candidate compounds are protective in relevant animal models of inhalational anthrax against the deadly Ames strain of Bacillus anthracis.
The specific aims of the study are: (1) Synthesis, purification and in vitro characterization of the three previously selected most active 2-cyclodextrin derivatives. (2) Development and validation of analytical methods for the detection of cyclodextrins in biological samples. (3) Efficacy testing of three selected compounds in mice challenged with Bacillus anthracis (Ames Strain) using an aerosol route of infection. (4) Testing of the toxicity and pharmacokinetic properties of the two most potent compounds in rabbits. (5) Efficacy testing of the compounds in rabbits challenged with Bacillus anthracis (Ames Strain) using an aerosol route of infection to select drug candidates with the best protective and pharmacokinetic properties and lowest toxicity. In the long-term, in-depth preclinical tests and a Phase 1 clinical trial in healthy adults to demonstrate the drug's safety and tolerability will lead to the development of a new anti-anthrax treatment.

Public Health Relevance

Bacillus anthracis is widely considered as one of the most likely biological weapons threats;however, there is currently no effective treatment for post-symptomatic inhalational anthrax. Traditional antibiotic therapy does not always work at this stage mainly because of the accumulation of anthrax toxin, which is considered a major virulence factor in anthrax infection. For this reason, there is an urgent need for the development of anti-toxin therapeutics, which could be administered after exposure as a supplement to traditional antibiotic intervention.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Small Business Innovation Research Grants (SBIR) - Phase II (R44)
Project #
2R44AI052894-04A1
Application #
7745053
Study Section
Special Emphasis Panel (ZRG1-IDM-Q (10))
Program Officer
Breen, Joseph J
Project Start
2002-09-01
Project End
2011-07-31
Budget Start
2009-08-01
Budget End
2010-07-31
Support Year
4
Fiscal Year
2009
Total Cost
$1,015,953
Indirect Cost
Name
Innovative Biologics, Inc
Department
Type
DUNS #
169174146
City
Herndon
State
VA
Country
United States
Zip Code
20171
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Diaz-Moscoso, Alejandro; Mendez-Ardoy, Alejandro; Ortega-Caballero, Fernando et al. (2011) Symmetry complementarity-guided design of anthrax toxin inhibitors based on ýý-cyclodextrin: Synthesis and relative activities of face-selective functionalized polycationic clusters. ChemMedChem 6:181-92
Yannakopoulou, Konstantina; Jicsinszky, Laszlo; Aggelidou, Crysie et al. (2011) Symmetry requirements for effective blocking of pore-forming toxins: comparative study with alpha-, beta-, and gamma-cyclodextrin derivatives. Antimicrob Agents Chemother 55:3594-7
Moayeri, Mahtab; Robinson, Tanisha M; Leppla, Stephen H et al. (2008) In vivo efficacy of beta-cyclodextrin derivatives against anthrax lethal toxin. Antimicrob Agents Chemother 52:2239-41
Karginov, Vladimir A; Nestorovich, Ekaterina M; Schmidtmann, Frank et al. (2007) Inhibition of S. aureus alpha-hemolysin and B. anthracis lethal toxin by beta-cyclodextrin derivatives. Bioorg Med Chem 15:5424-31
Karginov, Vladimir A; Nestorovich, Ekaterina M; Yohannes, Adiamseged et al. (2006) Search for cyclodextrin-based inhibitors of anthrax toxins: synthesis, structural features, and relative activities. Antimicrob Agents Chemother 50:3740-53