Drug therapy for celiac sprue

Abstract

Administering an effective dose of a tTGase inhibitor to a Celiac or dermatitis herpetiformis patient reduces the toxic effects of toxic gluten oligopeptides, thereby attenuating or eliminating the damaging effects of gluten.

1 - 7 . (canceled) 
     
     
         8 . A tTGase inhibitor that is a peptidase resistant polypeptide comprising one or more tTGase inhibitory moieties. 
     
     
         9 . The tTGase inhibitor of  claim 8 , wherein said tTGase inhibitory moiety is a glutamine analog. 
     
     
         10 . A tTGase inhibitory selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
       wherein R1, R2 and R3 are independently selected from H, alkyl, alkenyl, cycloalkyl, aryl, heteroalkyl, heteroaryl, alkoxy, alkylthio, aralkyl, aralkenyl, halo, haloalkyl, haloalkoxy, heterocyclyl, and heterocyclylalkyl groups, and wherein R1 and R2 can also be an amino acid, a peptide, a peptidomimetic, or a peptidic protecting group, and wherein R1 can additionally be selected from the group consisting of Cbz, Fmoc, Boc, PQP, Ac-PQP, PQPQLPYPQP, Ac-PQPQLPFPQP, QLQPFPQP, LQLQPFPQPLPYPQP, X 2-15 —P (where X 2-15  is a peptide consisting of any 2-15 amino acid residues followed by a N-terminal proline); R2 can additionally be selected from the group consisting of OMe, OtBu, Gly, Gly-NH 2 , LPY, LPF-NH 2 , LPYPQPQLPY, LPFPQPQLPF-NH 2 , LPYPQPQLP, LPYPQPQLPYPQPQPF, LP-X 2-15  (where X 2-15  is a peptide consisting of any 2-15 amino acid residues followed by a C-terminal proline); and R3 can additionally be a sulfonyl hydrazide (NHR′) where R′ is selected from H, alkyl, alkenyl, cycloalkyl, aryl, heteroalkyl, heteroaryl, alkoxy, alkylthio, aralkyl, aralkenyl, halo, haloalkyl, haloalkoxy, heterocyclyl, and heterocyclylalkyl group. 
     
     
         11 . The tTGase inhibitor of  claim 9 , wherein said glutenase resistant peptide is selected from the group consisting of: 
       
         
           
                 
               
                   PQPQLPY, PQPQLPYPQPQLP LQLQPFPQPQLPYPQPQLPYPQPQLPY 
                 
                     
                 
                   PQPQPF; QPQPFPPQLPYPQTQPFPPQQPYPQPQPQYPQPQ; 
                 
                     
                 
                   QQQPFPQQPIPQQPQPYPQQPQPYPQQPFPPQQPF; 
                 
                     
                 
                   QPFPQPQQTFPQQPQLPFPQQPQQPFPQPQ; VQWPQQQPVPQPHQPF, 
                 
                     
                 
                   VQGQGIIQPQQPA; FLQPQQPFPQQPQQPYPQQPQQPFPQ; 
                 
                     
                 
                   FSQPQQQFPQPQQPQQSFPQQQPP; 
                 
                     
                 
                   and QPFPQPQQPTPIQPQQPFPQRPQOPFPQPQ. 
                 
             
                
                
                
                
                
                
                
                
                
                
                
                
                
               
            
           
         
       
     
     
         12 . A tTGase inhibitor comprising:
 a compound that mimics a binding activity of tTGase reactive dipeptide having the amino acid sequence of XP; wherein said X is any amino acid.   
     
     
         13 . The tTGase inhibitor of  claim 12 , wherein X is selected from the group consisting of Q, L, Y and F. 
     
     
         14 - 21 . (canceled) 
     
     
         22 . A method of treating a neurological disorder, the method comprising:
 administering to a patient an effective dose of a tTGase inhibitor that is a peptidase resistant polypeptide comprising one or more tTGase inhibitory moieties.   
     
     
         23 . The method of  claim 22 , wherein said tTGase inhibitory moiety is a glutamine analog. 
     
     
         24 . A method of treating a neurological disorder, the method comprising:
 administering to a patient an effective dose of a tTGase inhibitor selected from the group consisting of:   
       
         
           
           
               
               
           
         
       
       wherein R1, R2 and R3 are independently selected from H, alkyl, alkenyl, cycloalkyl, aryl, heteroalkyl, heteroaryl, alkoxy, alkylthio, aralkyl, aralkenyl, halo, haloalkyl, haloalkoxy, heterocyclyl, and heterocyclylalkyl groups, and wherein R1 and R2 can also be an amino acid, a peptide, a peptidomimetic, or a peptidic protecting group, and wherein R1 can additionally be selected from the group consisting of Cbz, Fmoc, Boc, PQP, Ac-PQP, PQPQLPYPQP, Ac-PQPQLPFPQP, QLQPFPQP, LQLQPFPQPLPYPQP, X 2-15 —P (where X 2-15  is a peptide consisting of any 2-15 amino acid residues followed by a N-terminal proline); R2 can additionally be selected from the group consisting of OMe, OtBu, Gly, Gly-NH 2 , LPY, LPF-NH 2 , LPYPQPQLPY, LPFPQPQLPF-NH 2 , LPYPQPQLP, LPYPQPQLPYPQPQPF, LP-X 2-15  (where X 2-15  is a peptide consisting of any 2-15 amino acid residues followed by a C-terminal proline); and R3 can additionally be a sulfonyl hydrazide (NHR′) where R′ is selected from H, alkyl, alkenyl, cycloalkyl, aryl, heteroalkyl, heteroaryl, alkoxy, alkylthio, aralkyl, aralkenyl, halo, haloalkyl, haloalkoxy, heterocyclyl, and heterocyclylalkyl group. 
     
     
         25 . The method of  claim 22 , wherein said glutenase resistant peptide is selected from the group consisting of: 
       
         
           
                 
               
                   PQPQLPY, PQPQLPYPQPQLP LQLQPFPQPQLPYPQPQLPYPQPQLP 
                 
                     
                 
                   YPQPQPF; QPQPFPPQLPYPQTQPFPPQQPYPQPQPQYPQPQ; 
                 
                     
                 
                   QQQPFPQQPIPQQPQPYPQQPQPYPQQPFPPQQPF; 
                 
                     
                 
                   QPFPQPQQTFPQQPQLPFPQQPQQPFPQPQ; VQWPQQQPVPQPHQPF, 
                 
                     
                 
                   VQGQGIIQPQQPA; FLQPQQPFPQQPQQPYPQQPQQPFPQ; 
                 
                     
                 
                   FSQPQQQFPQPQQPQQSFPQQQPP; 
                 
                     
                 
                   and QPFPQPQQPTPIQPQQPFPQRPQQPFPQPQ. 
                 
             
                
                
                
                
                
                
                
                
                
                
                
                
                
               
            
           
         
       
     
     
         26 . The method of  claim 24 , wherein said tTGase inhibitor is a 3-halo-4,5-dihydroisoxazole.