Peptide inhibitors of tight junction permeability

Abstract

Novel compounds and methods for the inhibition of biological barrier permeability and for the inhibition of peptide translocation across biological barriers are identified. Assays for determining modulators of biological barrier permeability and for peptide translocation across biological barriers are provided. Methods for treating diseases relating to aberrant biological barrier permeability and peptide translocation across biological barriers are provided. Such diseases include celiac disease, necrotizing enterocolitis, diabetes, cancer, inflammatory bowel diseases, asthma, COPD, excessive or undesirable immune response, gluten sensitivity, gluten allergy, food allergy, rheumatoid arthritis, multiple sclerosis, immune-mediated or type 1 diabetes mellitus, systemic lupus erythematosus, psoriasis, scleroderma and autoimmune thyroid diseases.

What is claimed is: 
     
         1 . A peptide permeability inhibitor consisting of an amino acid sequence selected from the group consisting of SEQ ID NOs:1-162, wherein said peptide permeability inhibitor inhibits translocation of a gliadin-derived peptide across a biological barrier. 
     
     
         2 . The peptide of  claim 1 , wherein the peptide does not consist of an amino acid sequence selected from the group consisting of SEQ ID NOs: 15, 24 and 25. 
     
     
         3 . The peptide of  claim 1 , wherein the peptide consists of an amino acid sequence selected from the group consisting of SEQ ID NOs: 1-5, 10-17, 19-23, 27, 32, 34, 36, 48, 49, 55, 58, 67-77, 79-85, 87, 88, 91, 92, 94, 98-104, 106, 110, 111, 113-125, 127, 128, 147, 150, and 160-162. 
     
     
         4 . A method of inhibiting gliadin-derived peptide translocation across a biological barrier comprising contacting said barrier with a peptide permeability inhibitor consisting of an amino acid sequence selected from the group consisting of SEQ IDF NOs:1-162. 
     
     
         5 . The method of  claim 4 , wherein the peptide does not consist of an amino acid sequence selected from the group consisting of SEQ ID NOs: 15, 24 and 25. 
     
     
         6 . The method of  claim 4 , wherein the peptide consists of an amino acid sequence selected from the group consisting of SEQ ID NOs: 1-5, 10-17, 19-23, 27, 32, 34, 36, 48, 49, 55, 58, 67-77, 79-85, 87, 88, 91, 92, 94, 98-104, 106, 110, 111, 113-125, 127, 128, 147, 150, and 160-162. 
     
     
         7 . A composition for inhibiting gliadin-derived peptide translocation across a biological barrier, wherein said composition comprises a peptide permeability inhibitor consisting of an amino acid sequence selected from the group consisting of SEQ IDF NOs:1-162. 
     
     
         8 . The composition of  claim 7 , wherein the peptide does not consist of an amino acid sequence selected from the group consisting of SEQ ID NOs: 15, 24 and 25. 
     
     
         9 . The composition of  claim 7 , wherein the peptide consists of an amino acid sequence selected from the group consisting of SEQ ID NOs: 1-5, 10-17, 19-23, 27, 32, 34, 36, 48, 49, 55, 58, 67-77, 79-5, 87, 88, 91, 92, 94, 98-104, 106, 110, 111, 113-125, 127, 128, 147, 150, and 160-162. 
     
     
         10 . A method for inhibiting gliadin-derived peptide translocation across a biological barrier comprising administering to a subject in need thereof the composition of  claim 7  in an amount sufficient to inhibit said gliadin-derived peptide translocation. 
     
     
         11 . The method of  claim 10 , wherein the composition is administered in conjunction with an additional therapeutic agent. 
     
     
         12 . The method of  claim 11 , wherein the composition and the additional therapeutic agent are administered simultaneously. 
     
     
         13 . The method of  claim 11 , wherein the composition and the additional therapeutic agent are not administered simultaneously. 
     
     
         14 . The method of  claim 11 , wherein the composition further comprises the additional therapeutic agent. 
     
     
         15 . The method of  claim 11 , wherein the additional therapeutic agent is selected from the group consisting of aminosalicylates, corticosteroids, immunomodulators, antibiotics, cytokines, chemokines and biologic therapeutics. 
     
     
         16 . A peptide consisting of an amino acid sequence selected from the group consisting of SEQ IDF NOs:1-162, wherein said peptide inhibits a gliadin-induced increase in biological barrier permeability. 
     
     
         17 . The peptide of  claim 16 , wherein the peptide does not consist of an amino acid sequence selected from the group consisting of SEQ ID NOS: 15, 24 and 25. 
     
     
         18 . The peptide of  claim 16 , wherein the peptide consists of an amino acid sequence selected from the group consisting of SEQ ID NOs: 1-5, 10-17, 19-23, 27, 32, 34, 36, 48, 49, 55, 58, 67-77, 79-85, 87, 88, 91, 92, 94, 98-104, 106, 110, 111, 113-125, 127, 128, 147, 150, and 160-162. 
     
     
         19 . A method of inhibiting a gliadin-induced increase in biological barrier permeability comprising contacting said barrier with a peptide permeability inhibitor consisting of an amino acid sequence selected from the group consisting of SEQ IDF NOs:1-162. 
     
     
         20 . The method of  claim 19 , wherein the peptide does not consist of an amino acid sequence selected from the group consisting of SEQ ID NOs: 15, 24 and 25. 
     
     
         21 . The method of  claim 19 , wherein the peptide consists of an amino acid sequence selected from the group consisting of SEQ ID NOs: 1-5, 10-17, 19-23, 27, 32, 34, 36, 48, 49, 55, 58, 67-77, 79-85, 87, 88, 91, 92, 94, 98-104, 106, 110, 111, 113-125, 127, 128, 147, 150, and 160-162. 
     
     
         22 . A composition for inhibiting a gliadin-induced increase in biological barrier permeability, wherein said composition comprises a peptide permeability inhibitor consisting of an amino acid sequence selected from the group consisting of SEQ IDF NOS:1-162. 
     
     
         23 . The composition of  claim 22 , wherein the peptide does not consist of an amino acid sequence selected from the group consisting of SEQ ID NOs: 15, 24 and 25. 
     
     
         24 . The composition of  claim 22 , wherein the peptide consists of an amino acid sequence selected from the group consisting of SEQ ID NOs: 1-5, 10-17, 19-23, 27, 32, 34, 36, 48, 49, 55, 58, 67-77, 79-85, 87, 88, 91, 92, 94, 98-104, 106, 110, 111, 113-125, 127, 128, 147, 150, and 160-162. 
     
     
         25 . A method for inhibiting a gliadin-induced increase in biological barrier permeability comprising administering to a subject in need thereof the composition of  claim 22  in an amount sufficient to inhibit said increase in biological barrier permeability. 
     
     
         26 . The method of  claim 25 , wherein the composition is administered in conjunction with an additional therapeutic agent. 
     
     
         27 . The method of  claim 26 , wherein the composition and the additional therapeutic agent are administered simultaneously. 
     
     
         28 . The method of  claim 26 , wherein the composition and the additional therapeutic agent are not administered simultaneously. 
     
     
         29 . The method of  claim 26 , wherein the composition further comprises the additional therapeutic agent. 
     
     
         30 . The method of  claim 26 , wherein the additional therapeutic agent is selected from the group consisting of aminosalicylates, corticosteroids, immunomodulators, antibiotics, cytokines, chemokines and biologic therapeutics. 
     
     
         31 . A method of treating a patient with celiac disease, comprising administering to the patient a composition comprising a peptide that inhibits translocation of a gliadin-derived peptide across a biological barrier. 
     
     
         32 . The method of  claim 31 , wherein said composition comprises peptide consisting of an amino acid sequence selected from the group consisting of SEQ ID NOs:1-162. 
     
     
         33 . The method of  claim 32 , wherein the peptide does not consist of an amino acid sequence selected from the group consisting of SEQ ID NOs: 15, 24 and 25. 
     
     
         34 . The method of  claim 32 , wherein the peptide consists of an amino acid sequence selected from the group consisting of SEQ ID NOs: 1-5, 10-17, 19-23, 27, 32, 34, 36, 48, 49, 55, 58, 67-77, 79-85, 87, 88, 91, 92, 94, 98-104, 106, 110, 111, 113-125, 127, 128, 147, 150, and 160-162. 
     
     
         35 . The method of  claim 31 , wherein said composition further comprises an additional therapeutic agent selected from the group consisting of aminosalicylates, corticosteroids, immunomodulators, antibiotics, cytokines, chemokines and biologic therapeutics. 
     
     
         36 . A method of treating a patient with diabetes, comprising administering to the patient a composition comprising a peptide that inhibits a gliadin-induced increase in biological barrier permeability. 
     
     
         37 . The method of  claim 36 , wherein said composition comprises peptide consisting of an amino acid sequence selected from the group consisting of SEQ ID NOs:1-162. 
     
     
         38 . The method of  claim 37 , wherein the peptide does not consist of an amino acid sequence selected from the group consisting of SEQ ID NOs: 15, 24 and 25. 
     
     
         39 . The method of  claim 37 , wherein the peptide consists of an amino acid sequence selected from the group consisting of SEQ ID NOs: 1-5, 10-17, 19-23, 27, 32, 34, 36, 48, 49, 55, 58, 67-77, 79-85, 87, 88, 91, 92, 94, 98-104, 106, 110, 111, 113-125, 127, 128, 147, 150, and 160-162. 
     
     
         40 . The method of  claim 36 , wherein said composition further comprises an additional therapeutic agent selected from the group consisting of aminosalicylates, corticosteroids, immunomodulators, antibiotics, cytokines, chemokines and biologic therapeutics. 
     
     
         41 . A method of treating a patient with dermatitis herpetiformis, comprising administering to the patient a composition comprising a peptide that inhibits translocation of a gliadin-derived peptide across a biological barrier. 
     
     
         42 . The method of  claim 41 , wherein said composition comprises peptide consisting of an amino acid sequence selected from the group consisting of SEQ ID NOs:1-162. 
     
     
         43 . The method of  claim 42 , wherein the peptide does not consist of an amino acid sequence selected from the group consisting of SEQ ID NOs: 15, 24 and 25. 
     
     
         44 . The method of  claim 42 , wherein the peptide consists of an amino acid sequence selected from the group consisting of SEQ ID NOs: 1-5, 10-17, 19-23, 27, 32, 34, 36, 48, 49, 55, 58, 67-77, 79-85, 87, 88, 91, 92, 94, 98-104, 106, 110, 111, 113-125, 127, 128, 147, 150, and 160-162. 
     
     
         45 . the method of  claim 41 , wherein said composition further comprises an additional therapeutic agent selected from the group consisting of aminosalicylates, corticosteroids, immunomodulators, antibiotics, cytokines, chemokines and biologic therapeutics.