Peptide mimics of the cytokine receptor common gamma chain and methods and compositions for making and using the same

Abstract

Peptides which mimic a loop on the γ-chain that either interact with a cytokine or a γ-chain partner receptor chain of a heterodimeric cytokine receptor are disclosed. The peptides consist of 5-25 amino acids and inhibit signal transduction mediated by cytokine:receptor binding of cytokines that bind to receptors that comprise a γ-chain. Pharmaceutical compositions that comprise the peptides are disclosed. Methods of inhibiting signal transduction mediated by cytokine:receptor binding of cytokines that bind to receptors that comprise a γ-chain, methods of inhibiting cytokine mediated cell growth, proliferation, function or activity, methods of treating patients suffering from a disease disorder or condition characterized by cytokine mediated cell growth, proliferation, function or activity and methods of preventing a condition characterized by cytokine mediated cell growth, proliferation, function or activity are disclosed.

1 . A peptide which mimics a loop on the γ-chain that either interact with a cytokine or a γ-chain partner receptor chain of a heterodimeric cytokine receptor, wherein said peptide consists of 5-25 amino acids and inhibits signal transduction mediated by cytokine:receptor binding of cytokines that bind to receptors that comprise a γ-chain.  
     
     
         2 . The peptide of  claim 1  wherein said peptide includes: SEQ ID NO:1 IQLYQTF; SEQ ID NO:2 IHLYQTF; SEQ ID NO:3 CLQYLV; SEQ ID NO:4 CLEHLV; SEQ ID NO:5 CLQYLT; SEQ ID NO:6 CLEHLT; SEQ ID NO:7 CLQYLTQ; SEQ ID NO:8 CLEHLTQ; SEQ ID NO:9 PIAGSSQQ; SEQ ID NO:36 PICGSSQQ; SEQ ID NO:10 PLCGSAQH; SEQ ID NO:11 PLAGSAQH; SEQ ID NO:12 NHEPRFLS; SEQ ID NO:13 DYRHKFSL; SEQ ID NO:14 LNLQNL; SEQ ID NO:15 LKLQNL; SEQ ID NO:16 NLSESQL; SEQ ID NO:17 KLSEQL or such an amino acid sequence with one or more conservative substitutions.  
     
     
         3 . The peptide of  claim 1  wherein said peptide includes: SEQ ID NO:1 IQLYQTF; SEQ ID NO: 2 IHLYQTF; SEQ ID NO:3 CLQYLV; SEQ ID NO:4 CLEHLV; SEQ ID NO:5 CLQYLT; SEQ ID NO:6 CLEHLT; SEQ ID NO:7 CLQYLTQ; SEQ ID NO:8 CLEHLTQ; SEQ ID NO:9 PIAGSSQQ; SEQ ID NO:36 PICGSSQQ; SEQ ID NO:10 PLCGSAQH; SEQ ID NO:11 PLAGSAQH; SEQ ID NO:12 NHEPRFLS; SEQ ID NO:13 DYRHKFSL; SEQ ID NO:14 LNLQNL; SEQ ID NO:15 LKLQNL; SEQ ID NO:16 NLSESQL or SEQ ID NO:17 KLSEQL.  
     
     
         4 . The peptide of  claim 1  wherein said peptide includes: SEQ ID NO:1 IQLYQTF; SEQ ID NO: 2 IHLYQTF; SEQ ID NO:3 CLQYLV; SEQ ID NO:4 CLEHLV; SEQ ID NO:5 CLQYLT; SEQ ID NO:6 CLEHLT; SEQ ID NO:7 CLQYLTQ; SEQ ID NO:8 CLEHLTQ; SEQ ID NO:9 PIAGSSQQ; SEQ ID NO:36 PICGSSQQ; SEQ ID NO:10 PLCGSAQH; SEQ ID NO:11 PLAGSAQH; SEQ ID NO:12 NHEPRFLS; SEQ ID NO:13 DYRHKFSL; SEQ ID NO:14 LNLQNL; SEQ ID NO:15 LKLQNL; SEQ ID NO:16 NLSESQL; SEQ ID NO:17 KLSEQL or such an amino acid sequence with one or more conservative substitutions.  
     
     
         5 . The peptide of  claim 1  wherein said peptide is conformationally restricted.  
     
     
         6 . The peptide of  claim 1  wherein said peptide is cyclic.  
     
     
         7 . The peptide of  claim 1  wherein said peptide has a cysteine residue at its N terminus and a cysteine residue at its C terminus and it is cyclized by formation of a disulfide bond between said cysteine residues.  
     
     
         8 . The peptide of  claim 1  wherein said peptide is selected from the group consisting of: SEQ ID NO:18 CIQLYQTFC; SEQ ID NO:19 CIHLYQTFC; SEQ ID NO:20 CLQYLVC; SEQ ID NO:21 CLEHLVC; SEQ ID NO:22 CLQYLTC; SEQ ID NO:23 CLEHLTC; SEQ ID NO:24 CLQYLTQC; SEQ ID NO:25 CLEHLTQC; SEQ ID NO:26 CPIAGSSQQC; SEQ ID NO:37 CPICGSSQQC; SEQ ID NO:27 CPLCGSAQHC; SEQ ID NO:28 CPLAGSAQHC; SEQ ID NO:29 CNHEPRFLSC; SEQ ID NO:30 CDYRHKFSLC; SEQ ID NO:31 CLNLQNLC; SEQ ID NO:32 CLKLQNLC; SEQ ID NO:33 CNLSESQLC; SEQ ID NO:34 CKLSESQLC and derivative peptides thereof.  
     
     
         9 . The peptide of  claim 1  wherein said peptide is selected from the group consisting of: SEQ ID NO:18 CIQLYQTFC; SEQ ID NO:19 CIHLYQTFC; SEQ ID NO:20 CLQYLVC; SEQ ID NO:21 CLEHLVC; SEQ ID NO:22 CLQYLTC; SEQ ID NO:23 CLEHLTC; SEQ ID NO:24 CLQYLTQC; SEQ ID NO:25 CLEHLTQC; SEQ ID NO:26 CPIAGSSQQC; SEQ ID NO:37 CPICGSSQQC; SEQ ID NO:27 CPLCGSAQHC; SEQ ID NO:28 CPLAGSAQHC; SEQ ID NO:29 CNHEPRFLSC; SEQ ID NO:30 CDYRHKFSLC; SEQ ID NO:31 CLNLQNLC; SEQ ID NO:32 CLKLQNLC; SEQ ID NO:33 CNLSESQLC and SEQ ID NO:34 CKLSESQLC.  
     
     
         10 . The peptide of  claim 1  wherein said peptide is a conformationally restricted peptide having the formula:  
       R 1 —R 2 —R 3 —R 4 —R 5    
       wherein: 
 R 1  is a linking moiety;  
 R 2  is 0-10 amino acids;  
 R 3  is SEQ ID NO:1 IQLYQTF; SEQ ID NO: 2 IHLYQTF; SEQ ID NO:3 CLQYLV; SEQ ID NO:4 CLEHLV; SEQ ID NO:5 CLQYLT; SEQ ID NO:6 CLEHLT; SEQ ID NO:7 CLQYLTQ; SEQ ID NO:8 CLEHLTQ; SEQ ID NO:9 PIAGSSQQ; SEQ ID NO:36 PICGSSQQ; SEQ ID NO:10 PLCGSAQH; SEQ ID NO:11 PLAGSAQH; SEQ ID NO:12 NHEPRFLS; SEQ ID NO:13 DYRHKFSL; SEQ ID NO:14 LNLQNL; SEQ ID NO:15 LKLQNL; SEQ ID NO:16 NLSESQL; SEQ ID NO:17 KLSEQL or such an amino acid sequence with one or more conservative substitutions;  
 R 4  is 0-10 amino acids; and  
 R 5  is a linking moiety.  
 
     
     
         11 . The peptide of  claim 10  wherein: 
 R 1  is cysteine; and  
 R 5  is cysteine.  
 
     
     
         12 . The peptide of  claim 11  wherein: 
 R 3  is SEQ ID NO:1 IQLYQTF; SEQ ID NO: 2 IHLYQTF; SEQ ID NO:3 CLQYLV; SEQ ID NO:4 CLEHLV; SEQ ID NO:5 CLQYLT; SEQ ID NO:6 CLEHLT; SEQ ID NO:7 CLQYLTQ; SEQ ID NO:8 CLEHLTQ; SEQ ID NO:9 PIAGSSQQ; SEQ ID NO:36 PICGSSQQ; SEQ ID NO:10 PLCGSAQH; SEQ ID NO:11 PLAGSAQH; SEQ ID NO:12 NHEPRFLS; SEQ ID NO:13 DYRHKFSL; SEQ ID NO:14 LNLQNL; SEQ ID NO:15 LKLQNL; SEQ ID NO:16 NLSESQL; or SEQ ID NO:17 KLSEQL.  
 
     
     
         13 . The peptide of  claim 12  wherein: 
 R 1  is cysteine; and  
 R 5  is cysteine.  
 
     
     
         14 . A pharmaceutical composition comprising a peptide of  claim 1  and a pharmaceutically acceptable carrier or diluent.  
     
     
         15 . The pharmaceutical composition of  claim 14  wherein said peptide includes: SEQ ID NO:1 IQLYQTF; SEQ ID NO: 2 IHLYQTF; SEQ ID NO:3 CLQYLV; SEQ ID NO:4 CLEHLV; SEQ ID NO:5 CLQYLT; SEQ ID NO:6 CLEHLT; SEQ ID NO:7 CLQYLTQ; SEQ ID NO:8 CLEHLTQ; SEQ ID NO:9 PIAGSSQQ; SEQ ID NO:10 PLCGSAQH; SEQ ID NO:11 PLAGSAQH; SEQ ID NO:12 NHEPRFLS; SEQ ID NO:13 DYRHKFSL; SEQ ID NO:14 LNLQNL; SEQ ID NO:15 LKLQNL; SEQ ID NO:16 NLSESQL; SEQ ID NO:17 KLSEQL or such an amino acid sequence with one or more conservative substitutions.  
     
     
         16 . The pharmaceutical composition of  claim 14  wherein said peptide includes: SEQ ID NO:1 IQLYQTF; SEQ ID NO: 2 IHLYQTF; SEQ ID NO:3 CLQYLV; SEQ ID NO:4 CLEHLV; SEQ ID NO:5 CLQYLT; SEQ ID NO:6 CLEHLT; SEQ ID NO:7 CLQYLTQ; SEQ ID NO:8 CLEHLTQ; SEQ ID NO:9 PIAGSSQQ; SEQ ID NO:36 PICGSSQQ; SEQ ID NO:10 PLCGSAQH; SEQ ID NO:11 PLAGSAQH; SEQ ID NO:12 NHEPRFLS; SEQ ID NO:13 DYRHKFSL; SEQ ID NO:14 LNLQNL; SEQ ID NO:15 LKLQNL; SEQ ID NO:16 NLSESQL or SEQ ID NO:17 KLSEQL.  
     
     
         17 . The pharmaceutical composition of  claim 14  wherein said peptide is conformationally restricted.  
     
     
         18 . The pharmaceutical composition of  claim 14  wherein said peptide is cyclic.  
     
     
         19 . The pharmaceutical composition of  claim 14  wherein said peptide has a cysteine residue at its N terminus and a cysteine residue at its C terminus and it is cyclized by formation of a disulfide bond between said cysteine residues.  
     
     
         20 . The pharmaceutical composition of  claim 14  wherein said peptide is selected from the group consisting of: SEQ ID NO:18 CIQLYQTFC; SEQ ID NO:19 CIHLYQTFC; SEQ ID NO:20 CLQYLVC; SEQ ID NO:21 CLEHLVC; SEQ ID NO:22 CLQYLTC; SEQ ID NO:23 CLEHLTC; SEQ ID NO:24 CLQYLTQC; SEQ ID NO:25 CLEHLTQC; SEQ ID NO:26 CPIAGSSQQC; SEQ ID NO:37 CPICGSSQQC; SEQ ID NO:27 CPLCGSAQHC; SEQ ID NO:28 CPLAGSAQHC; SEQ ID NO:29 CNHEPRFLSC; SEQ ID NO:30 CDYRHKFSLC; SEQ ID NO:31 CLNLQNLC; SEQ ID NO:32 CLKLQNLC; SEQ ID NO:33 CNLSESQLC; SEQ ID NO:34 CKLSESQLC and derivative peptides thereof.  
     
     
         21 . The pharmaceutical composition of  claim 14  wherein said peptide is selected from the group consisting of: SEQ ID NO:18 CIQLYQTFC; SEQ ID NO:19 CIHLYQTFC; SEQ ID NO:20 CLQYLVC; SEQ ID NO:21 CLEHLVC; SEQ ID NO:22 CLQYLTC; SEQ ID NO:23 CLEHLTC; SEQ ID NO:24 CLQYLTQC; SEQ ID NO:25 CLEHLTQC; SEQ ID NO:26 CPIAGSSQQC; SEQ ID NO:37 CPICGSSQQC; SEQ ID NO:27 CPLCGSAQHC; SEQ ID NO:28 CPLAGSAQHC; SEQ ID NO:29 CNHEPRFLSC; SEQ ID NO:30 CDYRHKFSLC; SEQ ID NO:31 CLNLQNLC; SEQ ID NO:32 CLKLQNLC; SEQ ID NO:33 CNLSESQLC and SEQ ID NO:34 CKLSESQLC.  
     
     
         22 . The pharmaceutical composition of  claim 14  wherein said peptide is a conformationally restricted peptide having the formula:  
       R 1 —R 2 —R 3 —R 4 —R  
       wherein: 
 R 1  is a linking moiety;  
 R 2  is 0-10 amino acids;  
 R 3  is SEQ ID NO:1 IQLYQTF; SEQ ID NO: 2 IHLYQTF; SEQ ID NO:3 CLQYLV; SEQ ID NO:4 CLEHLV; SEQ ID NO:5 CLQYLT; SEQ ID NO:6 CLEHLT; SEQ ID NO:7 CLQYLTQ; SEQ ID NO:8 CLEHLTQ; SEQ ID NO:9 PIAGSSQQ; SEQ ID NO:36 PICGSSQQ; SEQ ID NO:10 PLCGSAQH; SEQ ID NO:11 PLAGSAQH; SEQ ID NO:12 NHEPRFLS; SEQ ID NO:13 DYRHKFSL; SEQ ID NO:14 LNLQNL; SEQ ID NO:15 LKLQNL; SEQ ID NO:16 NLSESQL; SEQ ID NO:17 KLSEQL or such an amino acid sequence with one or more conservative substitutions;  
 R 4  is 0-10 amino acids; and  
 R 5  is a linking moiety.  
 
     
     
         23 . The pharmaceutical composition of  claim 14  wherein: 
 R 1  is cysteine; and  
 R 5  is cysteine.  
 
     
     
         24 . The pharmaceutical composition of  claim 23  wherein: 
 R 3  is SEQ ID NO:1 IQLYQTF; SEQ ID NO: 2 IHLYQTF; SEQ ID NO:3 CLQYLV; SEQ ID NO:4 CLEHLV; SEQ ID NO:5 CLQYLT; SEQ ID NO:6 CLEHLT; SEQ ID NO:7 CLQYLTQ; SEQ ID NO:8 CLEHLTQ; SEQ ID NO:9 PIAGSSQQ; SEQ ID NO:36 PICGSSQQ; SEQ ID NO:10 PLCGSAQH; SEQ ID NO:11 PLAGSAQH; SEQ ID NO:12 NHEPRFLS; SEQ ID NO:13 DYRHKFSL; SEQ ID NO:14 LNLQNL; SEQ ID NO:15 LKLQNL; SEQ ID NO:16 NLSESQL; or SEQ ID NO:17 KLSEQL.  
 
     
     
         25 . The pharmaceutical composition of  claim 24  wherein: 
 R 1  is cysteine; and  
 R 5  is cysteine.  
 
     
     
         26 . A method of inhibiting signal transduction mediated by cytokine:receptor binding of cytokines that bind to receptors that comprise a y-chain, said method comprising the step of administering an effective amount of a peptide of  claim 1 .  
     
     
         27 . A method of inhibiting cytokine mediated cell growth, proliferation, function or activity comprising the step of contacting said cell with an peptide of  claim 1 .  
     
     
         28 . A method of treating a patient suffering from a disease disorder or condition characterized by cytokine mediated cell growth, proliferation, function or activity comprising the step of administering to said patient a therapeutically effective amount of a peptide of  claim 1 .  
     
     
         29 . A method of treating a patient suffering from a disease disorder or condition characterized by cytokine mediated cell growth, proliferation, function or activity comprising the step of administering to said patient a therapeutically effective amount of a peptide of  claim 1 , wherein said patient has lymphoma, leukemia, an allergic reaction, an autoimmune disease, graft versus host disease or rejection of a transplant or graft.  
     
     
         30 . A method of preventing a condition characterized by cytokine mediated cell growth, proliferation, function or activity in a patient identified as being at risk of such a condition comprising the step of administering to said patient a prophylactically effective amount of a peptide of  claim 1 .  
     
     
         31 . A method of preventing a condition characterized by cytokine mediated cell growth, proliferation, function or activity in a patient identified as being at risk of such a condition comprising the step of administering to said patient a prophylactically effective amount of a peptide of  claim 1 , wherein said patient is at risk of an allergic reaction, graft versus host disease or rejection of a transplant or graft.