Inhibitors of mammalian tight junction opening
The present invention provides novel peptides that inhibit and/or reduce the opening of mammalian tight junctions, i.e. peptide tight junction antagonists. The present invention also provides methods for the treatment of excessive or undesirable permeability of a tissue by administering to a subject suffering from such a condition a composition comprising a peptide tight junction antagonist of the invention.
1. A method of treating an excessive or undesirable permeability of a tissue containing tight junctions in a subject comprising:
administering to the subject a pharmaceutical composition comprising a peptide tight junction antagonist having three to five amino acids, and wherein the peptide is defined by the formula: X1-X2-X3-X4-X5; wherein:
X1 is optional, and where present is a natural or non-natural amino acid,
X2 is optional, and where present is a natural or non-natural amino acid,
X3 is a natural or non-natural amino acid,
X4 is selected from Pro and Ala, and
X5 is Gly, Gln, or Ala.
2. The method of claim 1 , wherein the subject has inflammatory bowel disease.
3. The method of claim 1 , wherein the subject has Crohn's disease.
4. The method of claim 1 , wherein the subject has ulcerative colitis.
5. The method of claim 1 , wherein the subject has Celiac Disease.
6. The method of claim 1 , wherein the subject has acute respiratory distress syndrome.
7. The method of claim 1 , wherein the subject has acute lung injury.
8. The method of claim 1 , wherein the subject has chronic obstructive pulmonary disorder.
9. The method of claim 1 , wherein the subject has asthma.
10. The method of claim 1 , wherein the subject has type I diabetes.
11. The method of claim 1 , wherein the pharmaceutical composition is a solution or powder aerosol for pulmonary delivery.
12. The method of claim 1 , wherein the pharmaceutical composition is formulated for enteric delivery.
13. The method of claim 1 , wherein the pharmaceutical composition is administered one or more times per day for a plurality of days.
14. The method of claim 1 , wherein the peptide has the amino acid sequence of SEQ ID NO: 4, 5, 6, 7, 8, 9, 10, 11, 13, 17, 18, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 34, or 35.