Peptide inhibitors of tight junction permeability
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.
1. A pharmaceutical composition comprising an effective amount of a peptide inhibitor of tight junction permeability of the sequence Gly-Gly-(d)Val-(d)Leu-(d)Val-(d)Gln-(d)Pro-Gly (SEQ ID NO:93), and one or more enteric agents that are stable in gastric fluid but dissolve in intestinal fluid.
2. The composition of claim 1 , wherein the composition substantially releases the peptide in the duodenum or the jejunum.
3. The composition of claim 2 , wherein the composition releases 30% or less of peptide in gastric fluid with a pH of 5 or less in approximately sixty minutes.
4. The composition of claim 2 , wherein the composition releases 70% or more of peptide in intestinal fluid with a pH of 5 or greater in approximately sixty minutes.
5. A method for inhibiting increased intestinal epithelial barrier permeability in a patient, comprising administering to said epithelial barrier in the patient the composition of claim 1 .
6. The method of claim 5 , wherein the patient has celiac disease.
7. The method of claim 5 , wherein the patient has Crohn's disease or ulcerative colitis (UC).
8. The method of claim 5 , wherein the subject has an autoimmune or inflammation-associated disease selected from the group consisting of diabetes, autoimmune hepatitis, multiple sclerosis, autism, dermatitis herpetiformis, IgA nephropathy, primary biliary cirrhosis, rheumatoid arthritis, systemic lupus erythematosus, Grave's disease, Hashimoto's disease, and depression.
9. The method of claim 5 , wherein the patient has necrotizing enterocolitis.