Compounds and methods for treating tight junction permeability

Abstract

The present invention provides Larazotide derivative compositions that resist protease degradation, and in various embodiments, do not demonstrate an inverse dose response, and/or can be delivered at higher doses without loss of potency or efficacy, thereby allowing improved therapy more desirable dosing schedules.

1 . A peptide promoting epithelial and/or endothelial tight junction integrity, the peptide comprising the amino acid sequence of SEQ ID NO:1, with one or two amino acid substitutions at the N-terminus, and optionally one or two amino acid substitutions of the C-terminus. 
     
     
         2 . The peptide of  claim 1 , having one or two amino acid substitutions at the N-terminus and one amino acid substitution at the C-terminus. 
     
     
         3 . The peptide of  claim 1 ,wherein the substitution is for a genetically-encoded or a non-genetically-encoded amino acid, and wherein the one or more substitutions are optionally D-amino acids. 
     
     
         4 . The peptide of  claim 3 , wherein the substitutions are for non-polar amino acids. 
     
     
         5 . The peptide of  claim 3 , wherein the substitution(s) are independently selected from alanine, valine, isoleucine, leucine, norleucine, norvaline, and allylgly. 
     
     
         6 . The peptide of  claim 3 , wherein at least one substitution is for an amino acid having a charged side chain. 
     
     
         7 . The peptide of  claim 3 , wherein a methionine (M) replaces one or both of the N terminal glycine residues of SEQ ID NO:1. 
     
     
         8 . A peptide promoting epithelial and/or endothelial tight junction integrity, the peptide comprising the addition of one amino acid to the N-terminus of the peptide of SEQ ID NO:1. 
     
     
         9 . The peptide of  claim 8 , wherein the peptide has the amino acid sequence: 
 MGGVLVQPG (SEQ ID NO:6), HGGVLVQPG (SEQ ID NO:7), FGGVLVQPG (SEQ ID NO:8), and LGGVLVQPG (SEQ ID NO:9).   
     
     
         10 . The peptide of  claim 1 , wherein the peptide comprises amino acid substitutions of at least one of the N terminal glycine residue, optionally in combination with a C-terminal extension of from 1 to 8 amino acids. 
     
     
         11 . The peptide of  claim 10 , wherein the peptide has the formula: X1-G2-V3-L4-V5-Q6-P7-G8 (SEQ ID NO:11), G1-X2-V3-L4-V5-Q6-P7-G8 (SEQ ID NO:12), X1-X2-V3-L4-V5-Q6-P7-G8 (SEQ ID NO:13), X1-G2-V3-L4-V5-Q6-P7-G8-X9-X10 (SEQ ID NO:14), and X1-X2-V3-L4-V5-Q6-P7-G8-X9-X10 (SEQ ID NO:15) wherein X is independently selected from genetically-encoded and non-genetically-encoded amino acids. 
     
     
         12 . A peptide promoting epithelial and/or endothelial tight junction integrity, the peptide comprising an addition of amino acid(s) to the N- and/or C-terminus with respect to the peptide of SEQ ID NO:1. 
     
     
         13 . The peptide of  claim 12 , wherein the N- and/or C-terminal extension amino acids are selected from non-polar amino acids. 
     
     
         14 . The peptide of  claim 13 , wherein the N- and/or C-terminal extension amino acids are independently elected from Ala, His, Ile, Leu, Met, Phe, Pro, Trp, Tyr, and Val. 
     
     
         15 . The peptide of  claim 12 , wherein the peptide has the formula (GG) n GGVLVQPG, where n=1 to 10 (SEQ ID NO: 16). 
     
     
         16 . The peptide of  claim 1 , wherein the peptide comprises one or more D-amino acids. 
     
     
         17 . The peptide of  claim 16 , wherein the peptide has one or two D-amino acids at the N-terminus and optionally the C-terminus, with all other non-Gly amino acids in the L configuration. 
     
     
         18 . The peptide of  claim 17 , wherein the peptide has the formula: (d)X1-G2-V3-L4-V5-Q6-P7-G8 (SEQ ID NO:18), G1-G2-V3-L4-V5-Q6-P7-(d)X8 (SEQ ID NO:19), (d)X1-(d)X2-V3-L4-V5-Q6-P7-G8 (SEQ ID NO:20), (d)X1-G2-V3-L4-V5-Q6-P7-(d)X8 (SEQ ID NO:21), (d)X1-(d)G2-V3-L4-V5-Q6-P7-(d)X8 (SEQ ID NO:22), and (d)X1-(d)X2-V3-L4-V5-Q6-(d)P7-(d)X8 (SEQ ID NO:23), where X is independently selected from any genetically or non-genetically-encoded amino acid other than Gly. 
     
     
         19 . The peptide of  claim 18 , wherein at least one X is an amino acid with a cyclic side chain, which are optionally selected from phenylalanine, tyrosine, histidine, proline, or tryptophan. 
     
     
         20 . A cyclic peptide promoting epithelial or endothelial tight junction integrity, the peptide comprising the amino acid sequence of SEQ ID NO:1, with one or two amino acid substitutions allowing for cyclization. 
     
     
         21 . The cyclic peptide of  claim 20 , wherein the peptide is cyclized by a disulfide bond between two Cysteine residues. 
     
     
         22 . The cyclic peptide of  claim 21 , wherein the peptide has the formula G1-G2-C-V3-L4-V5-Q6-P7-G8 (SEQ ID NO:24), (n-1)C-G1-G2-V3-L4-V5-Q6-P7-G8-9C (SEQ ID NO:24) and (n-3)C-(n-2)G-(n-1)G-G1-G2-V3-L4-V5-Q6-P7-G8-9C (SEQ ID NO:25). 
     
     
         23 - 40 . (canceled)