B-cyclodextrin derivatives and their use against anthrax lethal toxin

• US 20060247208A1
• Filed: 01/28/2005
• Published: 11/02/2006
• Est. Priority Date: 01/29/2004
• Status: Active Grant

• Current Assignee: Innovative Biologics, Inc.
• Original Assignee: Pinnacle Pharmaceuticals, Inc.
• Inventors: Fahmi, Noureddine, Hecht, Sidney, Karginov, Vladimir, Alibek, Ken
• Granted Patent: US 7,851,457 B2
• Time in Patent Office: Days
• US Class Current: 514/58
• CPC Class Codes: A61K 31/724 Cyclodextrins
• CPC Class Codes: A61P 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 31/04 Antibacterial agents
• CPC Class Codes: A61P 31/12 Antivirals
• CPC Class Codes: A61P 39/02 Antidotes
• CPC Class Codes: C08B 37/0012 Cyclodextrin [CD], e.g. cycle with 6 units (alpha), with 7 units (beta) and with 8 units (gamma), large-ring cyclodextrin or cycloamylose with 9 units or more; Derivatives thereof

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 derivates 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.

Claims

1. A compound according to the formula

2. The compound according to claim 1, wherein R₆ is NH₂, SCH₂CH₂NH₂, SCH₂CH₂CH₂NH₂, or SCH₂CH₂CH₂CH₂NH₂.

3. The compound according to claim 1 selected from the group consisting of compounds 1-9 and 12-14 as shown in FIG. 1.

4. A method for inhibiting anthrax toxicity in a cell, comprising contacting the cell with a compound according to claim 1.

5. A method for inhibiting anthrax toxicity in a cell, comprising contacting the cell with a compound according to claim 2.

6. A method for inhibiting anthrax toxicity in a cell, comprising contacting the cell with a compound according to claim 1.

9. A method for inhibiting a virulence factor that is a protein forming a trans-membrane channel with sevenfold symmetry for α

-toxin of S. aureus comprising contacting a cell with a compound according to claim 1.

10. A method for inhibiting a virulence factor that is a protein forming a trans-membrane channel with sevenfold symmetry for α

-toxin of S. aureus comprising contacting a cell with a compound according to claim 2.

11. A method for inhibiting a virulence factor that is a protein forming a trans-membrane channel with sevenfold symmetry for α

-toxin of S. aureus comprising contacting a cell with a compound according to claim 3.

7. (canceled)

8. A method for inhibiting anthrax toxin activity comprising administering a cyclic compound with a sevenfold symmetry and a diameter between 12 Å

and 35 Å

.

12. A method for inhibiting a virulence factor that is a protein forming a trans-membrane channel with sixfold symmetry for Heliobacter pylori Vac A toxin comprising contacting a cell with a derivative of hexameric β

-cyclodextrin.

13. A method for inhibiting a virulence factor that is a protein forming a trans-membrane channel with sixfold symmetry for Hepatitis C virus p7 protein comprising contacting a cell with a derivative of hexameric β

-cyclodextrin.

14. A compound according to the formula

15. The compound according to claim 14, wherein R₆ is SCH₂CH₂NH₂, SCH₂CH₂CH₂NH₂, or SCH₂CH₂CH₂CH₂NH₂.

16. The compound according to claim 14 selected from the group consisting of compounds 10 and 11 as shown in FIG. 1.