B-cyclodextrin derivatives and their use against anthrax lethal toxin

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.

1 - 3 . (canceled) 
     
     
         4 . A method for inhibiting anthrax toxicity in a cell, comprising contacting the cell with a compound according to the formula 
       
         
           
           
               
               
           
         
       
       wherein R 2  is H, OH, OAc, OMe, or O(CH 2 CH 2 O) n ; R 3  is H, OH, OAc, OMe, OSO 3 Na, or NH 2 ; and R 6  is H, NH 2 , SCH 2 CH 2 NH 2 , SCH 2 CH 2 CH 2 NH 2 , SCH 2 CH 2 CH 2 CH 2 NH 2 , I, N 3 , SH, lower alkyl, S-alkylguanidyl, O-alkylguanidyl, S-aminoalkyl, O-aminoalkyl, aminoalkyl, aralkyl, aryl, heterocyclic ring(s), or OSO 3 Na. 
     
     
         5 . The method according to claim  1 , wherein R 6  is NH 2 , SCH 2 CH 2 NH 2 , SCH 2 CH 2 CH 2 NH 2 , or SCH 2 CH 2 CH 2 CH 2  NH 2 . 
     
     
         6 . A method for inhibiting anthrax toxicity in a cell, comprising contacting the cell with a compound shown in  FIG. 1 . 
     
     
         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. 
     
     
         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 the formula 
       
         
           
           
               
               
           
         
         wherein R 2  is H, OH, OAc, OMe, or O(CH 2 CH 2 O)n; R 3  is H, OH, OAc, OMe, OSO 3 Na, or NH 2 ; and R 6  is H, NH 2 , SCH 2 CH 2 NH 2 , SCH 2 CH 2 CH 2 NH 2 , SCH 2 CH 2 CH 2 CH 2 NH 2 , I, N 3 , SH, lower alkyl, S-alkylguanidyl, O-alkylguanidyl, S-aminoalkyl, O-aminoalkyl, aminoalkyl, aralkyl, aryl, heterocyclic ring(s), or OSO 3 Na. 
       
     
     
         10 . The method according to  claim 9 , wherein R 6  is NH 2 , SCH 2  CH 2 NH 2 , SCH 2 CH 2 CH 2 NH 2 , or SCH 2 CH 2 CH 2 CH 2 NH 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 shown in  FIG. 1 . 
     
     
         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.