Drug therapy for Celiac Sprue

Abstract

Celiac Sprue and/or dermatitis herpetiformis are treated by interfering with HLA binding of immunogenic gluten peptides. The antigenicity of gluten oligopeptides and the ill effects caused by an immune response thereto are decreased by administration of an HLA-binding peptide inhibitor. Such inhibitors are analogs of immunogenic gluten peptides and (i) retain the ability to bind tightly to HLA molecules; (ii) retain the proteolytic stability of these peptides; but (iii) are unable to activate disease-specific T cells.

1 . An HLA-binding peptide inhibitor; wherein said inhibitor is an analog of an immunogenic gluten oligopeptide of at least about 8 residues in length, wherein the immunogenic gluten oligopeptide is altered by the replacement of one or more amino acids; and wherein said analog binds tightly to HLA molecules; is proteolytically stable; and does not activate disease-specific T cells.  
     
     
         2 . The HLA-binding peptide inhibitor of  claim 1 , wherein said analog comprises one or more naturally occurring amino acids, non-naturally occurring amino acids, modified amino acids, or amino acid mimetics.  
     
     
         3 . The HLA-binding peptide inhibitor of  claim 2 , wherein said analog is further derivatized to reduce the affinity of the analog for disease-specific T cell receptors.  
     
     
         4 . The HLA-binding peptide inhibitor of  claim 1 , wherein said immunogenic gluten oligopeptides comprises at least one PXP motif.  
     
     
         5 . The HLA-binding peptide inhibitor of  claim 1 , wherein said immunogenic gluten oligopeptides comprises a sequence selected from the group consisting of: PQPELPY; PFPQPELPYP, PQPELPYPQPQLP, PQQSFPEQQPP, VQGQGIIQPEQPAQ, FPEQPQQPYPQQP, FPQQPEQPYPQQP, FSQPEQEFPQPQ; PFPQPQLPY, PQPQLPYPQ, PFPQPELPY; PYPQPELPY and PYPQPQLPY.  
     
     
         6 . The HLA-binding peptide inhibitor of  claim 1 , wherein said inhibitor comprises the sequence PXPQPELPY, where X is Tyr, Trp, Arg, Lys, p-iodo-Phe, 3-iodo-Tyr, p-amino-Phe, 3-amino-Tyr, hydroxylysine, ornithine, Asp or Glu.  
     
     
         7 . The HLA-binding peptide inhibitor of  claim 6 , wherein said inhibitor is further derivatized to reduce the affinity of the analog for disease-specific T cell receptors.  
     
     
         8 . The HLA-binding peptide inhibitor of  claim 6 , wherein said inhibitor is further modified to increase binding potency to an MHC molecule.  
     
     
         9 . The HLA-binding peptide inhibitor of  claim 1 , wherein said inhibitor comprises the sequence PFPQX 1 ELX 2 Y, where X 1  and X 2  are independently selected from 4-hydroxy-Pro, 4-amino-Pro, or 3-hydroxy-Pro, and proline, with the proviso that at least one of X 1  and X 2  is a residue other than proline  
     
     
         10 . The HLA-binding peptide inhibitor of  claim 9 , wherein said inhibitor is further derivatized to reduce the affinity of the analog for disease-specific T cell receptors.  
     
     
         11 . The HLA-binding peptide inhibitor of  claim 9 , wherein said inhibitor is further modified to increase binding potency to an MHC molecule.  
     
     
         12 . A method of treating Celiac Sprue and/or dermatitis herpetiformis, the method comprising: 
 administering to a patient an effective dose of an HLA-binding peptide inhibitor;    wherein said HLA-binding peptide inhibitor attenuates gluten toxicity in said patient.    
     
     
         13 . The method of  claim 12 , wherein said HLA-binding peptide inhibitor is administered with a glutenase.  
     
     
         14 . The method according to  claim 12 , wherein said HLA-binding peptide inhibitor is administered orally.  
     
     
         15 . The method according to  claim 12 , wherein said HLA-binding peptide inhibitor is contained in a formulation that comprises an enteric coating.  
     
     
         16 . A formulation for use in treatment of Celiac Sprue and/or dermatitis herpetiformis, comprising: 
 an effective dose of an HLA-binding peptide inhibitor and a pharmaceutically acceptable excipient.    
     
     
         17 . The formulation according to  claim 16 , further comprising an enteric coating.  
     
     
         18 . Use of an HLA-binding peptide inhibitor in the treatment of HLA-DQ2 positive individuals who are either pre-disposed to type I diabetes or have developed symptoms of type I diabetes.  
     
     
         19 . A computer for producing a three-dimensional representation of a molecule wherein said molecule comprises an HLA-DQ2 molecule bound to an immunogenic gluten oligopeptide, wherein said computer comprises: 
 a machine-readable data storage medium comprising a data storage material encoded with machine-readable data, wherein said data comprises the three-dimensional coordinates of a subset of the atoms in an HLA-DQ2 molecule bound to an immunogenic gluten oligopeptide;    a working memory for storing instructions for processing said machine-readable data;    a central-processing unit coupled to said working memory and to said machine-readable data storage medium for processing said machine readable data into said three-dimensional representation; and    a display coupled to said central-processing unit for displaying said three-dimensional representation.    
     
     
         20 . A computer-assisted method for identifying potential modulators of Celiac Sprue and/or dermatitis herpetiformis, using a programmed computer comprising a processor, a data storage system, an input device, and an output device, comprising the steps of: 
 (a) inputting into the programmed computer through said input device data comprising the three-dimensional coordinates of a subset of the atoms in an HLA-DQ2 molecule bound to an immunogenic gluten oligopeptide, thereby generating a criteria data set;    (b) comparing, using said processor, said criteria data set to a computer database of chemical structures stored in said computer data storage system;    (c) selecting from said database, using computer methods, chemical structures having a portion that is structurally similar to said criteria data set;    (d) outputting to said output device the selected chemical structures having a portion similar to said criteria data set.