Tight junction protein modulators and uses thereof

Abstract

The invention provides tight junction protein modulators, compositions comprising the same, and uses thereof. In particular, the invention provides tight junction protein modulators that modulate the second extracellular loop of tight junction proteins, such as occludin or claudin.

1 . A method for treating a clinical condition associated with abnormal growth or development of cells in a subject, said method comprising administering to the subject in need of such a treatment a composition comprising a therapeutically effective amount of a compound comprising FYNP amino acid sequence, wherein F is phenylalanine, tyrosine, tryptophan, or leucine; Y is tyrosine, phenylalanine, tryptophan, or leucine; N is asparagine or glutamine; and P is proline. 
     
     
         2 . The method of  claim 1 , wherein the compound stimulates apoptosis of cells. 
     
     
         3 . The method of  claim 1 , wherein the cells comprise epithelial cells. 
     
     
         4 . The method of  claim 1 , wherein the clinical condition associated with abnormal growth or development of cells comprises skin cancer, breast cancer, ovarian cancer, or metastases thereof. 
     
     
         5 . The method of  claim 1 , wherein the compound comprises D-amino acids or retro-inverso D-amino acids. 
     
     
         6 . A method for modulating apoptosis of cells comprising contacting the cells with an effective amount of a compound comprising FYNP amino acid sequence or a retro-inverso amino acid thereof, wherein F is phenylalanine, tyrosine, tryptophan, or leucine; Y is tyrosine, phenylalanine, tryptophan, or leucine; N is asparagine or glutamine; and P is proline. 
     
     
         7 . The method of  claim 6 , wherein the cells comprises epithelial cells. 
     
     
         8 . The method of  claim 6 , wherein the compound modulates an adhesion protein. 
     
     
         9 . The method of  claim 8 , wherein the adhesion protein comprises occludin, claudin, junction adhesion molecule, integrins, or a combination thereof. 
     
     
         10 . The method of  claim 9 , wherein the compound comprises at least 3 consecutive amino acid sequences of the second extracellular loop sequence of occludin or claudin, or a derivative thereof. 
     
     
         11 . The method of  claim 6 , wherein the compound comprises D-amino acids or retro-inverso D-amino acids. 
     
     
         12 . The method of  claim 6 , wherein the compound comprises about 20 amino acid sequences or less and is a cyclic peptide or a linear peptide, or a derivative thereof. 
     
     
         13 . The method of  claim 12 , wherein the compound is a cyclic compound of the formula: 
       
         
           
           
               
               
           
         
       
       wherein
 each of X 1  and X 4  is independently cysteine, glutamic acid, aspartic acid, lysine, or ornithine; 
 each of L 1  and L 4  is independently the corresponding functional group of the amino acid side chain of X 1  and X 4 , respectively, or —(CH 2 ) m —, wherein m is an integer from 1 to 4; 
 each of X 2  and X 3  is glycine; 
 each n is independently 0, 1 or 2; 
 Z is glycine, isoleucine, alanine, leucine, lysine, methionine, cysteine, phenylalanine, threonine, tryptophan, valine, proline, serine, tyrosine, arginine, or histidine; 
 F is phenylalanine, tyrosine, tryptophan, or leucine; 
 Y is tyrosine, phenylalanine, tryptophan, or leucine; 
 N is asparagine or glutamine; and 
 P is proline. 
 
     
     
         14 . The method of  claim 13 , wherein F is phenylalanine, Y is tyrosine, N is asparagines, and Z is glycine. 
     
     
         15 . The method of  claim 13 , wherein X 1  and X 4  are cysteine. 
     
     
         16 . The method of  claim 15 , wherein L 1  and L 2  together form a moiety of the formula —S—S—. 
     
     
         17 . A compound comprising 20 amino acid sequences or less and comprises D-amino acid sequences or retro-inverso D-amino acid sequences of FYNP, wherein F is phenylalanine, tyrosine, tryptophan, or leucine; Y is tyrosine, phenylalanine, tryptophan, or leucine; N is asparagine or glutamine; and P is proline. 
     
     
         18 . The compound of  claim 17 , wherein said compound comprises a cyclic peptide or a linear peptide. 
     
     
         19 . The compound of  claim 18 , wherein said cyclic peptide is of the formula: 
       
         
           
           
               
               
           
         
       
       wherein
 each of X 1  and X 4  is independently cysteine, glutamic acid, aspartic acid, lysine, or ornithine; 
 each of L 1  and L 4  is independently the corresponding functional group of the amino acid side chain of X 1  and X 4 , respectively, or —(CH 2 ) m —, wherein m is an integer from 1 to 4; 
 each of X 2  and X 3  is glycine; 
 each n is independently 0, 1 or 2; 
 Z is glycine, isoleucine, alanine, leucine, lysine, methionine, cysteine, phenylalanine, threonine, tryptophan, valine, proline, serine, tyrosine, arginine, or histidine; and 
 F, Y, N, and P are those defined in  claim 17 . 
 
     
     
         20 . The compound of  claim 19 , wherein Z is glycine, and L 1  and L 2  together form a moiety of the formula —S—S—.