Interleukin-1 receptor antagonists, compositions, and methods of treatment

Abstract

Peptides that are designed to inhibit the biological activity of the IL-1R type 1 receptor and inhibit IL-1R/IL-1RacP related cell signaling and biological activity are disclosed. Compositions comprising IL-1R antagonists of the present invention are useful in the treatment of IL-1 related diseases or conditions such as arthritis, rheumatoid arthritis, osteoarthritis, and inflammatory bowel disease as well as other chronic or acute inflammatory diseases. This invention also discloses an isolated compound having an IL-1R antagonist activity, said compound being selected from the group consisting of: a peptide comprising the amino acid sequence RYTPELX, wherein R, Y, T, P, E, L, refer to their corresponding amino acids, and X is selected from no amino acid and alanine (A); and a derivative of (a) wherein the derivative incorporates one, two or three amino acid modification selected from an amino acid addition, deletion or substitution in the RYTPEL portion of the peptide, and wherein said derivative maintains its antagonist IL-1R activity.

1 - 38 . (canceled) 
     
     
         39 . A method of treating a disease, disorder or condition associated with IL-1 or IL-1R function in a subject, the method comprising
 administering a peptide into the subject in need of treatment, wherein the peptide is 5 to 25 amino acids long and contains an amino acid sequence that includes at least four amino acids from RYTVELA (SEQ ID NO: 10) and wherein the at least four amino acids maintain their relative positions as they appear in RYTVELA (SEQ ID NO: 10).   
     
     
         40 . The method of  claim 39 , wherein the peptide is 5 to 16 amino acids long. 
     
     
         41 . The method of  claim 39 , wherein the peptide is 5 to 9 amino acids long. 
     
     
         42 . The method of  claim 39 , wherein the amino acid sequence includes at least five amino acids from RYTVELA (SEQ ID NO: 10) and wherein the at least five amino acids maintain their relative positions as they appear in RYTVELA (SEQ ID NO: 10). 
     
     
         43 . The method of  claim 39 , wherein the peptide is 6 to 25 amino acids long and the amino acid sequence includes at least six amino acids from RYTVELA (SEQ ID NO: 10) and wherein the at least six amino acids maintain their relative positions as they appear in RYTVELA (SEQ ID NO: 10). 
     
     
         44 . The method of  claim 39 , wherein the amino acid sequence is selected from the group consisting of: RYTPEL (SEQ ID NO:21), RYTVQLA (SEQ ID NO:15), KYTPELA (SEQ ID NO:22), RYTPDLA (SEQ ID NO:25), RYTVELA (SEQ ID NO:10), RYVVELA (SEQ ID NO:18), RWTPELA (SEQ ID NO:24), RYTVEL (SEQ ID NO:20), RYTPEL (SEQ ID NO:39), RWTPEL (SEQ ID NO:34), PRYTVELA (SEQ ID NO:9), APRYTVALA (SEQ ID NO:7), RYTPEV (SEQ ID NO:35), YTVELA (SEQ ID NO: 11), TVELA (SEQ ID NO: 12), and RFTPEL (SEQ ID NO:36). 
     
     
         45 . The method of  claim 39 , wherein the peptide comprises one or more modifications to increase protease resistance, serum stability and/or bioavailability. 
     
     
         46 . The method of  claim 45 , wherein the one or more modifications are selected from N- and/or C-terminal acetylation, glycosylation, biotinylation, substitution with D-amino acid, or un-natural amino acid, and/or cyclization of the peptide. 
     
     
         47 . The method of  claim 46 , wherein the peptide contains at least one D-amino acid. 
     
     
         48 . The method of  claim 39 , wherein the disease, disorder or condition is an acute or chronic inflammatory disease, disorder or condition. 
     
     
         49 . The method of  claim 39 , wherein the disease, disorder or condition is selected from rheumatoid arthritis, Crohn's disease, ulcerative colitis, osteoarthritis, psoriasis, inflammatory bowel disease, septic shock, stroke, encephalitis, respiratory distress syndrome, and/or meningitis. 
     
     
         50 . The method of  claim 39 , wherein the peptide is administered orally. 
     
     
         51 . A method of treating a disease, disorder or condition associated with IL-1 or IL-1R function in a subject, the method comprising
 administering a peptide into the subject in need of treatment, wherein the peptide is 5 to 25 amino acids long and contains an amino acid sequence that is at least 70% identical to RYTVELA (SEQ ID NO: 10).   
     
     
         52 . The method of  claim 51 , wherein the amino acid sequence is at least 85% identical to RYTVELA (SEQ ID NO:10). 
     
     
         53 . The method of  claim 51 , wherein the peptide is 5 to 16 amino acids long. 
     
     
         54 . The method of  claim 51 , wherein the peptide is 5 to 9 amino acids long. 
     
     
         55 . A method of treating a disease, disorder or condition associated with IL-1 or IL-1R function in a subject, the method comprising
 administering a peptide into the subject in need of treatment, wherein the peptide is a non-competitive inhibitor of the IL-1 receptor and contains an amino acid sequence that includes at least four amino acids from RYTVELA (SEQ ID NO: 10) and wherein the at least four amino acids maintain their relative positions as they appear in RYTVELA (SEQ ID NO: 10).   
     
     
         56 . A method comprising
 administering a peptide determined to be a non-competitive inhibitor of the IL-1 receptor into a cell system expressing the IL-1 receptor thereby inhibiting, reducing or preventing an IL-1 associated function in the cell system,   wherein the peptide contains an amino acid sequence that includes at least four amino acids from RYTVELA (SEQ ID NO:10) and wherein the at least four amino acids maintain their relative positions as they appear in RYTVELA (SEQ ID NO: 10).   
     
     
         57 . The method of  claim 56 , wherein the cell system is an in vitro system. 
     
     
         58 . The method of  claim 56 , wherein the cell system is an ex vivo system. 
     
     
         59 . The method of  claim 56 , wherein the cell system is an in vivo system. 
     
     
         60 . The method of  claim 59 , wherein the in vivo system is an animal model. 
     
     
         61 . The method of  claim 59 , wherein the in vivo system is a human subject. 
     
     
         62 . The method of  claim 56 , wherein the IL-1 associated function comprises PGE 2  synthesis. 
     
     
         63 . The method of  claim 56 , wherein the IL-1 associated function is involved in an inflammatory reaction. 
     
     
         64 . The method of  claim 56 , wherein the peptide is 5 to 25 amino acids long. 
     
     
         65 . The method of  claim 56 , wherein the peptide is 5 to 16 amino acids long. 
     
     
         66 . The method of  claim 56 , wherein the peptide is 5 to 9 amino acids long. 
     
     
         67 . A peptide that is 5 to 25 amino acids long and has an amino acid sequence that includes at least four amino acids from RYTVELA (SEQ ID NO: 10) and wherein the at least four amino acids maintain their relative positions as they appear in RYTVELA (SEQ ID NO: 10), and further wherein the peptide contains one or more D-amino acids. 
     
     
         68 . The peptide of  claim 67 , wherein the amino acid sequence includes at least five amino acids from RYTVELA (SEQ ID NO: 10) and wherein the at least five amino acids maintain their relative positions as they appear in RYTVELA (SEQ ID NO: 10). 
     
     
         69 . The peptide of  claim 67 , wherein the peptide is in natural or in inverse configuration. 
     
     
         70 . The peptide of  claim 67 , wherein the peptide contains a mixture of L-amino acid and D-amino acid. 
     
     
         71 . A peptide that is 5 to 25 amino acids long and has an amino acid sequence that is at least 70% identical to RYTVELA (SEQ ID NO: 10), and wherein the peptide contains one or more D-amino acids.