Selective peptide antagonists

Abstract

Methods and compositions related to the selective, specific disruption of multiple ligand-receptor signaling interactions, such as ligand-receptor interactions implicated in disease, are disclosed. These interactions may involve multiple cytokines in a single receptor family or multiple ligand receptor interactions from at least two distinct ligand-receptor families. The compositions may comprise polypeptides having composite sequences that comprise sequence fragments of two or more ligand binding sites. The methods and compositions may involve sequence fragments of two or more ligand binding sites that are arranged to conserve the secondary structure of each of the ligands from which the sequence fragments were taken.

1 . A nucleotide sequence encoding a cross-family inhibitory polypeptide, wherein the cross-family inhibitory polypeptide comprises at least two therapeutic composite peptides; wherein each of the at least two therapeutic composite peptides inhibits an activity of at least two cytokines selected from a family of cytokines that bind to a common receptor; wherein the family of cytokines is selected from the group consisting of γc-family of cytokines, IL-6 family of cytokines, and IL-17 family of cytokines, wherein each of the at least two therapeutic composite peptides comprises a region 1-20 amino acids in length that aligns with a corresponding region of a target ligand or receptor having a sequence of any one of SEQ ID NO:122, SEQ ID NO:123, SEQ ID NO:125, SEQ ID NO:126, SEQ ID NO:127, SEQ ID NO:128, SEQ ID NO:129, SEQ ID NO:142, SEQ ID NO:143, SEQ ID NO:145, SEQ ID NO:146, SEQ ID NO:147, SEQ ID NO:148, SEQ ID NO:155, SEQ ID NO:156, SEQ ID NO:158, SEQ ID NO:159, SEQ ID NO:160, and SEQ ID NO:161 
     
     
         2 . The nucleotide sequence of  claim 1 , wherein the nucleotide sequence further comprises a sequence encoding a polypeptide linker sequence. 
     
     
         3 . The nucleotide sequence of  claim 2 , wherein the polypeptide linker sequence is selected from the group consisting of SEQ ID NO:132, SEQ ID NO:151, and SEQ ID NO:154. 
     
     
         4 . The nucleotide sequence of  claim 1 , wherein each of the at least two encoded therapeutic composite peptides inhibits two or more members of at least one family of cytokines selected from the group consisting of γc-family of cytokines, IL-6 family of cytokines, and IL-17 family of cytokines. 
     
     
         5 . The nucleotide sequence of  claim 1 , wherein each of the at least two encoded therapeutic composite peptides inhibits two or more members of at least two families of cytokines selected from the group consisting of γc-family of cytokines, IL-6 family of cytokines, and IL-17 family of cytokines. 
     
     
         6 . The nucleotide sequence of  claim 1 , wherein the 7c-family of cytokines consists of IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21; the IL-6 family of cytokines consists of IL-6, IL-11, CNTF, CT-1, OSM, LIF, and IL-27; and the IL-17 family of cytokines consists of IL-17A, IL-17B, IL-17C, IL-17D, IL-17E (IL-25), and IL-17F. 
     
     
         7 . The nucleotide sequence of  claim 1 , wherein the nucleotide sequence is selected from the group consisting of dsDNA, ssDNA, dsRNA, and ssRNA. 
     
     
         8 . The nucleotide sequence of  claim 1 , wherein the nucleotide sequence further comprises a sequence encoding a signal peptide. 
     
     
         9 . A genetic construct comprising:
 a nucleotide sequence encoding a cross-family inhibitory polypeptide; and   at least one regulatory element, wherein the at least one regulatory element is configured to regulate expression of the cross-family inhibitory polypeptide;   wherein the cross-family inhibitory polypeptide comprises at least two therapeutic composite peptides, wherein each of the at least two therapeutic composite peptides inhibits an activity of at least two cytokines selected from a family of cytokines that bind to a common receptor; wherein the family of cytokines is selected from the group consisting of γc-family of cytokines, IL-6 family of cytokines, and IL-17 family of cytokines, wherein each of the at least two therapeutic composite peptides comprises a region 1-20 amino acids in length that aligns with a corresponding region of a target ligand or receptor having a sequence of any one of SEQ ID NO:122, SEQ ID NO:123, SEQ ID NO:125, SEQ ID NO:126, SEQ ID NO:127, SEQ ID NO:128, SEQ ID NO:129, SEQ ID NO:142, SEQ ID NO:143, SEQ ID NO:145, SEQ ID NO:146, SEQ ID NO:147, SEQ ID NO:148, SEQ ID NO:155, SEQ ID NO:156, SEQ ID NO:158, SEQ ID NO:159, SEQ ID NO:160, and SEQ ID NO:161.   
     
     
         10 . The genetic construct of  claim 9 , wherein the genetic construct is DNA. 
     
     
         11 . The genetic construct of  claim 9 , wherein the genetic construct is RNA. 
     
     
         12 . The genetic construct of  claim 9 , wherein the nucleotide sequence further comprises a sequence encoding a polypeptide linker sequence. 
     
     
         13 . The genetic construct of  claim 12 , wherein the polypeptide linker sequence is selected from the group consisting of SEQ ID NO:132, SEQ ID NO:151, and SEQ ID NO:154. 
     
     
         14 . The genetic construct of  claim 9 , wherein each of the at least two encoded therapeutic composite peptides inhibits two or more members of at least two families of cytokines selected from the group consisting of γc-family of cytokines, IL-6 family of cytokines, and IL-17 family of cytokines. 
     
     
         15 . The genetic construct of  claim 9 , wherein the 7c-family of cytokines consists of IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21; the IL-6 family of cytokines consists of IL-6, IL-11, CNTF, CT-1, OSM, LIF, and IL-27; and the IL-17 family of cytokines consists of IL-17A, IL-17B, IL-17C, IL-17D, IL-17E (IL-25), and IL-17F. 
     
     
         16 . A pharmaceutical composition comprising:
 a nucleotide sequence encoding a cross-family inhibitory polypeptide; and   a pharmaceutical acceptable carrier, diluent, excipient or combination thereof;   wherein the cross-family inhibitory polypeptide comprises at least two therapeutic composite peptides, wherein each of the at least two therapeutic composite peptides inhibits an activity of at least two cytokines selected from a family of cytokines that bind to a common receptor; wherein the family of cytokines is selected from the group consisting of γc-family of cytokines, IL-6 family of cytokines, and IL-17 family of cytokines, wherein each of the at least two therapeutic composite peptides comprises a region 1-20 amino acids in length that aligns with a corresponding region of a target ligand or receptor having a sequence of any one of SEQ ID NO:122, SEQ ID NO:123, SEQ ID NO:125, SEQ ID NO:126, SEQ ID NO:127, SEQ ID NO:128, SEQ ID NO:129, SEQ ID NO:142, SEQ ID NO:143, SEQ ID NO:145, SEQ ID NO:146, SEQ ID NO:147, SEQ ID NO:148, SEQ ID NO:155, SEQ ID NO:156, SEQ ID NO:158, SEQ ID NO:159, SEQ ID NO:160, and SEQ ID NO:161.   
     
     
         17 . The pharmaceutical composition of  claim 16 , wherein the nucleotide sequence is selected from the group consisting of dsDNA, ssDNA, dsRNA, and ssRNA. 
     
     
         18 . The pharmaceutical composition of  claim 16 , wherein each of the at least two encoded therapeutic composite peptides inhibits two or more members of at least two families of cytokines selected from the group consisting of 7c-family of cytokines, IL-6 family of cytokines, and IL-17 family of cytokines. 
     
     
         19 . The pharmaceutical composition of  claim 16 , wherein the 7c-family of cytokines consists of IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21; the IL-6 family of cytokines consists of IL-6, IL-11, CNTF, CT-1, OSM, LIF, and IL-27; and the IL-17 family of cytokines consists of IL-17A, IL-17B, IL-17C, IL-17D, IL-17E (IL-25), and IL-17F.