Chemokine analogs for the treatment of human diseases

Abstract

The present invention is concerned with chemokine analogs, including IL-8 analogs, IP-10 analogs, MIP-1α analogs, RANTES analogs, I-309 analogs, MCP-1 analogs, and CCL28 analogs, that are useful for the treatment of a variety of diseases and disorders, and as an adjunct to the treatment of a variety of diseases and disorders. A therapeutically effective amount of the chemokine analog may be administered to a patient in need of such treatment.

1 .- 11 . (canceled)  
   
   
       12 . An I-309 mimetic comprising an N-terminal region and a C-terminal region, wherein the I-309 mimetic has a total of about 10 to about 34 amino acid residues, and 
 the N-terminal region comprises a conserved amino acid sequence selected from a group consisting of SEQ ID NO:972, variant, e1, and conservative amino acid substitutions thereof, and has the following general structure:                          (SEQ ID NO:972)                           RNH-Lys-Ser-Met-Gln-Val-Pro-Phe-Ser-Arg-Ala-                       (OH)NH 2 ;                                     wherein, R is an N-terminal modifier comprising a component selected from a group consisting of a hydrogen, a poly(ethylene glycol) or derivative thereof, a diagnostic label, an acyl group, an acetyl group, and a modifier capable of reducing the ability of the I-309 mimetic to act as a substrate for aminopeptidases; and, the (OH)NH 2  is a hydroxy or amine group that comprises the C-terminal region or attaches to any combination of up to 7 additional amino acid residues that attach to a linker that attaches to the C-terminal region, wherein the C-terminal region consists of amino acid residues 52-64 of SEQ ID NO:5; and,    the linker is (1) H 2 N—Z A —COOH, wherein Z A  is selected from the group consisting of saturated and unsaturated aliphatics consisting of 20 or fewer carbon atoms that are optionally substituted with a hydroxyl, carboxyl, carbonyl, thiol, amino, amido, imino, or aromatic group having from 5 to 7 members in the ring; and —(CH 2 ) n —, wherein n is an integer ranging from 9 to 14; or (2) any combination of four natural amino acids.    
   
   
       13 . The compound of  claim 12 , wherein the linker is 11-aminoundecanoic acid.  
   
   
       14 . The composition of  claim 12 , wherein R comprises a poly(ethylene glycol), a glycosaminoglycan, or derivative thereof, each having a molecular weight of less than about 20,000 Daltons.  
   
   
       15 . The composition of  claim 12 , wherein the conserved amino acid sequence is selected from a group consisting of SEQ ID NO:1635 and conservative amino acid substitutions thereof, and has the following general structure:  
     
       
         
               
               
             
                   
               
                 (SEQ ID NO:1635) 
                   
               
               
               
             
                 H 2 N-Lys-Ser-Met-Gln-Val-Pro-Phe-Ser-Arg-Ala-NH 2 . 
                   
               
                   
               
           
              
              
             
          
           
              
              
             
          
         
       
     
   
   
       16 . The composition of  claim 12 , wherein the conserved amino acid sequence composes the first 10 amino acid residues of the I-309 mimetic.  
   
   
       17 . The composition of  claim 12 , wherein the C-terminal region is cyclized at Glu 57  and Lys 61 .  
   
   
       18 . The composition of  claim 12 , wherein the I-309 mimetic is selected from a group consisting of SEQ ID NO:972, variant e1, and conservative amino acid substitutions thereof, and has the following general structure:  
     
       
         
               
               
             
                   
               
                 (SEQ ID NO:972) 
                   
               
               
               
               
             
                   
                 RNH-Lys-Ser-Met-Gln-Val-Pro-Phe-Ser-Arg-Ala- 
                   
               
                   
                   
               
                   
                 (OH)NH 2 ; 
               
                   
                   
               
           
              
              
             
          
           
              
              
              
              
             
          
         
       
     
   
   
       19 . An I-309 mimetic comprising an N-terminal region and a C-terminal region, wherein the I-309 mimetic has a total of about 15 to about 25 amino acid residues, and the N-terminal region or C-terminal region comprises a conserved amino acid sequence selected from a group consisting of SEQ ID NO:973, variant e2, and conservative amino acid substitutions thereof, and has the following general structure:  
     
       
         
               
               
             
                   
               
                 (SEQ ID NO:973) 
                   
               
               
               
             
                 RNH-Ala-Phe-Ser-Phe-Ala-Glu-Gln-Glu-Ile-Pro-Leu- 
                   
               
                   
               
                 Arg-Ala-Ile-Leu-(OH)NH 2 ; 
               
                   
               
           
              
              
             
          
           
              
              
              
              
             
          
         
       
     
     wherein, R is an N-terminal region or an N-terminal modifier comprising a component selected from a group consisting of a hydrogen, a poly(ethylene glycol) or derivative thereof, a diagnostic label, an acyl group, an acetyl group, and a modifier capable of reducing the ability of the I-309 mimetic to act as a substrate for aminopeptidases; and, the (OH)NH 2  is a hydroxy  
     or amine group that comprises the C-terminal region, or attaches to any combination of additional amino acid residues composing the C-terminal region; and,  
     the I-309 mimetic consists essentially of the conserved amino acid sequence and from 0 to 10 additional amino acid residues of any combination.  
   
   
       20 . The composition of  claim 19 , wherein R comprises a poly(ethylene glycol), a glycosaminoglycan, or derivative thereof, each having a molecular weight of less than about 20,000 Daltons.  
   
   
       21 . The composition of  claim 19 , wherein the conserved amino acid sequence is selected from a group consisting of SEQ ID NO:1636 and conservative amino acid substitutions thereof, and has the following general structure:  
     
       
         
               
               
             
                   
               
                 (SEQ ID NO:1636) 
                   
               
               
               
             
                 H 2 N-Ala-Phe-Ser-Phe-Ala-Glu-Gln-Glu-Ile-Pro-Leu- 
                   
               
                   
               
                 Arg-Ala-Ile-Leu-NH 2 . 
               
                   
               
           
              
              
             
          
           
              
              
              
              
             
          
         
       
     
   
   
       22 . The composition of  claim 19 , wherein the conserved amino acid sequence composes the first 15 amino acid residues of the I-309 mimetic.  
   
   
       23 . The composition of  claim 19 , wherein the conserved amino acid sequence is selected from a group consisting of SEQ ID NO:974, variant e3, and conservative amino acid substitutions thereof, and has the following general structure:  
     
       
         
               
               
             
                   
               
                 (SEQ ID NO:974) 
                   
               
               
               
             
                 RNH-Ala-Phe-Ser-Phe-Ala-Glu-Gln-Glu-Ile-Pro-Leu- 
                   
               
                   
               
                 Arg-Ala-Ile-Leu-Cys-Tyr-Arg-Asn-Thr-Ser-Ser-Ile- 
               
                   
               
                 (OH)NH 2 . 
               
                   
               
           
              
              
             
          
           
              
              
              
              
              
              
             
          
         
       
     
   
   
       24 . The composition of  claim 19 , wherein the I-309 mimetic is selected from a group consisting of SEQ ID:1637 and conservative amino acid substitutions thereof, and has the following structure:  
     
       
         
               
               
             
                   
               
                 (SEQ ID NO:1637) 
                   
               
               
               
             
                 H 2 N-Ala-Phe-Ser-Phe-Ala-Glu-Gln-Glu-Ile-Pro-Leu- 
                   
               
                   
               
                 Arg-Ala-Ile-Leu-Cys-Tyr-Arg-Asn-Thr-Ser-Ser-Ile- 
               
                   
               
                 NH 2 . 
               
                   
               
           
              
              
             
          
           
              
              
              
              
              
              
             
          
         
       
     
   
   
       25 . The composition of  claim 19 , wherein the I-309 mimetic is selected from a group consisting of SEQ ID NO:973, variant e2, and conservative amino acid substitutions thereof, and has the following general structure:  
     
       
         
               
               
             
                   
               
                 (SEQ ID NO:973) 
                   
               
               
               
             
                 RNH-Ala-Phe-Ser-Phe-Ala-Glu-Gln-Glu-Ile-Pro-Leu- 
                   
               
                   
               
                 Arg-Ala-Ile-Leu-(OH)NH 2 . 
               
                   
               
           
              
              
             
          
           
              
              
              
              
             
          
         
       
     
   
   
       26 . The composition of  claim 19 , wherein the I-309 mimetic is selected from a group consisting of SEQ ID NO:974, variant e3, and conservative amino acid substitutions thereof, and has the following general structure:  
     
       
         
               
               
             
                   
               
                 (SEQ ID NO:974) 
                   
               
               
               
             
                 RNH-Ala-Phe-Ser-Phe-Ala-Glu-Gln-Glu-Ile-Pro-Leu- 
                   
               
                   
               
                 Arg-Ala-Ile-Leu-Cys-Tyr-Arg-Asn-Thr-Ser-Ser-Ile- 
               
                   
               
                 (OH)NH 2 . 
               
                   
               
           
              
              
             
          
           
              
              
              
              
              
              
             
          
         
       
     
   
   
       27 . An I-309 mimetic comprising an N-terminal region and a C-terminal region, wherein the N-terminal region or C-terminal region comprises a conserved amino acid sequence selected from a group consisting of SEQ ID NO:975, variant e4, and conservative amino acid substitutions thereof, and has the following general structure:  
     
       
         
               
               
             
                   
               
                 (SEQ ID NO:975) 
                   
               
               
               
             
                 RNH-Ala-Tyr-Arg-Asn-Thr-Ser-Ser-Ile-Cys-Ser-Asn- 
                   
               
                   
               
                 Glu-Gly-Leu-Ile-Phe-Lys-Leu-Lys-Arg-Gly-Lys-Glu- 
               
                   
               
                 Ala-(OH)NH 2 ; 
               
                   
               
           
              
              
             
          
           
              
              
              
              
              
              
             
          
         
       
     
     wherein, R is an N-terminal modifier comprising a component selected from a group consisting of a hydrogen, a poly(ethylene glycol) or derivative thereof, a diagnostic label, an acyl group, an acetyl group, and a modifier capable of reducing the ability of the I-309 mimetic to act as a substrate for aminopeptidases; and, the (OH)NH 2  is a hydroxy or amine group that comprises  
     the C-terminal region, or attaches to any combination of additional amino acid residues composing the C-terminal region; and,  
     the I-309 mimetic consists essentially of the conserved amino acid sequence and from 0 to 10 additional amino acid residues of any combination.  
   
   
       28 . The composition of  claim 27 , wherein R comprises a poly(ethylene glycol), a glycosaminoglycan, or derivative thereof, each having a molecular weight of less than about 20,000 Daltons.  
   
   
       29 . A method of increasing an I-309-mediated activity of a cell having an I-309 receptor comprising binding the I-309 receptor of the cell with the I-309 mimetic of  claim 13 .  
   
   
       30 . A method of increasing an I-309-mediated activity of a cell having an I-309 receptor comprising binding the I-309 receptor of the cell with the I-309 mimetic of  claim 20 .  
   
   
       31 . A method of increasing an I-309-mediated activity of a cell having an I-309 receptor comprising binding the I-309 receptor of the cell with the I-309 mimetic of  claim 28.