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B-cyclodextrin derivatives and their use against anthrax lethal toxin

a technology of b-cyclodextrin and anthrax, which is applied in the direction of antibacterial agents, antinoxious agents, drug compositions, etc., can solve the problems of reducing ineffective and less attractive antibodies as potential drugs, so as to reduce the effectiveness of antibiotic treatment and effective treatment of inhalational anthrax

Inactive Publication Date: 2009-01-01
INNOVATIVE BIOLOGICS
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

"The invention provides new treatments to help fight antibiotic-resistant bacteria like anthrax. The first treatment involves small molecules that can stop the pore formed by a protein called PA, which is necessary for the action of anthrax toxin. The second treatment involves methods for inhibiting the toxic effects of Bacillus anthrasis by contacting cells with these small molecules. The third treatment involves novel methods for making certain derivatives of β-CD, which is a molecule used in the first treatment."

Problems solved by technology

Currently, there is no effective treatment for inhalational anthrax, beyond the administration of antibiotics shortly after exposure.
Time delay reduces the effectiveness of antibiotic treatment.
Although promising, antibodies are less attractive as potential drugs in comparison with low molecular weight compounds, which offer potentially better penetration through membranes and are not sensitive to proteases.

Method used

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  • B-cyclodextrin derivatives and their use against anthrax lethal toxin
  • B-cyclodextrin derivatives and their use against anthrax lethal toxin
  • B-cyclodextrin derivatives and their use against anthrax lethal toxin

Examples

Experimental program
Comparison scheme
Effect test

example 1

Synthesis of β-cyclodextrin Derivatives

[0034]Reagents. β-cyclodextrin derivatives 1-7 listed in Table 1 were synthesized at Pinnacle Pharmaceuticals, Inc. (Charlottesville, Va.). Compounds 12 and 13 were purchased from Cytrea Ltd (Dublin, Ireland). Sulfo derivatives of β-cyclodextrin 8-11 were kindly provided by Dr. Gyula Vigh (Texas A&M University, College Station, Tex.). β-cyclodextrin 14 was purchased from Sigma (St. Louis, Mo.). Most chemical reagents were purchased from Aldrich Chemicals or Fisher Scientific and used without further purification. Acetonitrile and dichloromethane were distilled from CaH2. DMF was distilled from CaH2 under diminished pressure. Triethylamine was distilled from P205.

[0035]Analysis. 1H NMR and 13C NMR spectra were recorded on a General Electric QE-300 or a Varian 300 spectrometer. Moisture sensitive reactions were conducted under argon in oven-dried glassware. Analytical thin-layer chromatography was performed on Merk 60F254 precoated silica gel pla...

example 2

Protection of Cells from Cytotoxicity

[0036]Recombinant B. anthracis lethal factor (rLF), edema factor (rEF), and protective antigen (rPA) were acquired from List Biological Laboratories, Inc. (Campbell, Calif.). Murine RAW 264.7 monocyte-macrophage cell line ATCC TIB-71 was obtained from American Type Culture Collection (Manassas, Va., USA). The cells were cultured in phenol free Dulbecco's Modification of Eagle's Medium / Ham's F-12 50 / 50 Mix (Mediatech, Inc., Herndon, Va., USA) supplemented with 10% heat-inactivated fetal bovine serum, 100 units / ml: 100 μg / ml penicillin-streptomycin, 0.1 mM non-essential amino acids, and 0.5 mM 2-mercaptoethanol at 37° C. in 5% CO2. The cells were harvested using Cellstripper™ from Mediatech, Inc. and then were washed once with media to remove the non-enzymatic dissociation solution. RAW 264.7 cells were plated in 96-well flat-bottomed tissue culture plates from Becton Dickinson (San Jose, Calif., USA) at a concentration of 105 cells / well in the DME...

example 3

Inhibition of Ion Conductance

[0037]Ion conductance experiments were performed according to Montal and Mueller [14] with modifications [15,16]. PA channels were reconstituted into planar lipid membranes formed from DPhPC; the membrane bathing solution contained 0.1M KCl, 1 mM EDTA at pH 6.6. Ion conductance through PA channels was measured in the presence of PrAmBC.

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Abstract

The invention provides low molecular weight compounds that block the pore formed by protective antigen and inhibit anthrax toxin action. Structures of the compounds are derivatives of β-cyclodextrin. Per-substituted alkylamino derivatives displayed inhibitory activity, and they were protective against anthrax lethal toxin action at low micromolar concentrations. Also, the addition of one of the alkylamino derivatives to the bilayer lipid membrane with multiple PA channels caused a significant decrease in membrane conductance. Thus, the invention also provides methods for protection against anthrax toxicity.

Description

[0001]This application claims priority to U.S. patent application Ser. No. 11 / 045,423, filed on Jan. 28, 2005, the contents of which are incorporated herein by reference in its entirety.[0002]This work was supported by grant IR43AI052894-01 from the National Institute of Allergy and Infectious Diseases. The government has certain rights in this invention.BACKGROUND OF THE INVENTION[0003]1. Field of the Invention[0004]The invention relates to protection against Anthrax-mediated biotoxicity.[0005]2. Summary of the Related Art[0006]Bacillus anthracis is one of the most dangerous potential biological weapons. Currently, there is no effective treatment for inhalational anthrax, beyond the administration of antibiotics shortly after exposure. Time delay reduces the effectiveness of antibiotic treatment. Dixon et al., Anthrax. N. Engl. J. Med.: 341, 815-826 (1999) teaches that major factors playing a role in anthrax infection are the cytotoxic effect of anthrax toxin, and bacteremia leadin...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/724A61P31/04A61P31/12
CPCC08B37/0012A61K31/724A61P1/04A61P31/04A61P31/12A61P39/02
Inventor HECHT, SIDNEYFAHMI, NOUREDDINE
Owner INNOVATIVE BIOLOGICS
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