BLOCKERS OF PORE-FORMING VIRULENCE FACTORS AND THEIR USE AS ANTI-INFECTIVES

20120277184

13/463810

May 03, 2012

The invention provides methods for treating, delaying, and preventing pathological conditions caused by pore-forming toxins such as anthrax toxin, α-hemolysin toxin, and ε-toxin using a class of low molecular weight compounds that block the pore formed by these toxins. Specific compounds useful for treating, preventing, or delaying a disease condition caused by Bacillus anthracis, Staphylococcus aureus, and Clostridium perfringens are identified.

KARGINOV, VLADIMIR (Ashburn, VA, US)

Innovative biologics, Inc (Herndon, VA, US)

1. A method for treating, preventing or delaying a disease condition in a subject by interfering with the pathogenesis of a causal agent of the condition, comprising: administering an effective amount of a pharmaceutical composition to the subject, wherein said pharmaceutical composition is one comprising a chemical substance having a shape complementary to a pore formed by an oligomeric toxin of the causal agent, said chemical substance having the following formula: [chemical expression included] wherein R2 is H, OH; R3 is H, OH, OAc, OMe, OSO3Na or NH2; and R6 is NH2, SCH2CH2NH2, SCH2CH2CH2NH2, SCH2CH2CH2CH2NH2, 1, N3, SH, lower alkyl, S-alkylguanidyl, O-alkylguanidyl, S-aminoalkyl, O-aminoalkyl, aminoalkyl, aralkyl, aryl, heterocyclic ring(s), or OSO3Na, or R2 is OMe; R3 is OMe; and R6 is H, SCH2CH2NH2, SCH2CH2CH2NH2, SCH2CH2CH2CH2NH2, I, SH, lower alkyl, S-alkylguanidyl, O-alkylguanidyl, S-aminoalkyl, O-aminoalkyl, aminoalkyl, aralkyl, aryl, heterocyclic ring(s); and wherein said causal agent is one selected from the group consisting of Hepatitis C virus, an influenza virus, poliovirus, Sindbis virus, human respiratory syncytial virus, Semliki forest virus, Ross river virus, Clostridium perfringens, Clostridium difficile, Escherichia coli, Staphylococcus aureus, Bacillus anthracis, Aeromonas hydrophilia, Helicobacter pylori, Vibrio cholerae, Pseudomonas aeruginosa, Clostridium septicum, HIV and Bacillus sphaericus, Streptococcus pneumoniae, Streptococcus pyogenes, Clostridium botulinum, and Mycobacterium tuberculosis.

2. The method of claim 1, wherein said causal agent is selected from the group consisting of Bacillus anthracis, Staphylococcus aureus, and Clostridium perfringens.

3. The method of claim 1, wherein said pathogen is Staphylococcus aureus, and said compound is one in which R2 is OH, R3 is OH, and R6 is selected from the group consisting of, [chemical expression included]

4. The method of claim 1, wherein said pathogen is Staphylococcus aureus, and said compound is one in which R2 is OH, R3 is OH, and R6 is [chemical expression included]

5. The method of claim 1, wherein said pathogen is Bacillus anthracis, and said compound is in which R2 is OH, R3 is OH, and R6 is selected from the group consisting of [chemical expression included] S(CH2)8NH2.

6. The method of claim 1, wherein said pathogen is Bacillus anthracis, and said compound is in which R2 is OH, R3 is OH, and R6 is S(CH2)8NH2.

7. The method of claim 1, wherein said pathogen is Clostridium perfringens, and said compound is one in which R2 is OH, R3 is OH, and R6 selected from [chemical expression included]

8. The method of claim 1, wherein said pathogen is Clostridium perfringens, and said compound is one in which R2 is OH, R3 is OH, and R6 is [chemical expression included]

9. A method of treating, delaying or preventing a disease condition in a subject caused by α-HL or ε-toxin, comprising: administering to said subject a composition comprising a compound having the formula: [chemical expression included] wherein n=6, R2═R3═H, and R6═NH2, [chemical expression included] or n=7, R2═R3=−(CH2)3NH2, and R6═OH; or n=7, R2═R3═OH, and R6═ [chemical expression included] and —N—(CH2)4—CH3.

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edspap.20120277184