Results from our SBIR Phase I project demonstrated that beta-cyclodextrin derivatives designed to block the trans-membrane channel formed by B. anthracis protective antigen (PA) can inhibit the cytotoxic effects of anthrax toxin at low micromolar concentrations. Based on successful completion of the feasibility study, the overall goal of our Phase II project is to select the best drug candidates for anthrax treatment. To achieve this goal we will perform large-scale design, synthesis and screening of chemical libraries, and test the best candidates in small animal studies.
The specific aims of this Phase II study are: (1) Utilize crystallographic coordinates and initial testing data in concert with computational chemistry to design additional beta-cyclodextrin derivatives with increased affinity to the PA pore. (2) Optimize a cell-based assay to screen the inhibition of the anthrax toxin cytotoxic effect, establish and validate cell-based and biochemical assays to test chemical compounds for the ability to block the PA channel. (3) Synthesize representative libraries of beta-cyclodextrin analogues, and screen them using biochemical and cell-based assays. (4) Perform toxicity and efficacy tests in mice using at least five compounds with inhibitory activity at nanomolar concentrations to select drug candidates. Long term goals include subsequent preclinical and clinical studies that will lead to the development of a new anti-anthrax treatment.

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 #
2R44AI052894-02
Application #
6791534
Study Section
Special Emphasis Panel (ZRG1-SSS-Q (10))
Program Officer
Baker, Phillip J
Project Start
2002-09-01
Project End
2006-04-30
Budget Start
2004-05-15
Budget End
2005-04-30
Support Year
2
Fiscal Year
2004
Total Cost
$791,069
Indirect Cost
Name
Innovative Biologics, Inc
Department
Type
DUNS #
169174146
City
Herndon
State
VA
Country
United States
Zip Code
20171
Karginov, Vladimir A (2013) Cyclodextrin derivatives as anti-infectives. Curr Opin Pharmacol 13:717-25
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