Metal-binding compounds and uses therefor

Abstract

The invention provides a method of reducing the damage done by reactive oxygen species (ROS) in an animal. The invention also provides a method of reducing the concentration of a metal in an animal. These methods comprise administering to the animal an effective amount of a metal-binding compound as further described in the application. The invention further provides a method of reducing the damage done by ROS to a cell, a tissue or an organ that has been removed from an animal. This method comprising contacting the cell, tissue or organ with a solution or medium containing an effective amount of a metal-binding compound of the invention. The invention further provides novel metal-binding compounds, pharmaceutical compositions comprising the metal-binding compounds, and kits comprising a container holding a metal-binding compound of the invention.

1 - 500 . (canceled) 
     
     
         501 . A peptide whose sequence is:
   P 1 -P 2 ,   
       wherein:
 P 1  is:
 Xaa 1  Xaa 2  His or 
 Xaa 1  Xaa 2  His Xaa 3 ; 
 
 Xaa 1  is glycine, alanine, valine, leucine, isoleucine, serine, threonine, aspartic acid, isoaspartic acid, asparagine, glutamic acid, isoglutamic acid, glutamine, lysine, hydroxylysine, histidine, arginine, ornithine, phenylalanine, tyrosine, tryptophan, cysteine, methionine, or α-hydroxymethylserine, and the only substituents on the α-amino group of Xaa 1  are hydrogen; 
 Xaa 2  is glycine, alanine, β-alanine, valine, leucine, isoleucine, serine, threonine, aspartic acid, asparagine, glutamic acid, glutamine, lysine, hydroxylysine, histidine, arginine, ornithine, phenylalanine, tyrosine, tryptophan, cysteine, methionine, or α-hydroxymethylserine; and 
 Xaa 3  is glycine, alanine, valine, leucine, isoleucine, lysine, histidine, arginine, ornithine, aspartic acid, glutamic acid, asparagine, glutamine or tryptophan; and 
 P 2  is a peptide sequence which comprises a sequence of a Cu(I) binding site, and P 2  contains no more than 10 amino acids; 
 or a physiologically-acceptable salt of the peptide. 
 
     
     
         502 . The peptide of  claim 501  wherein:
 Xaa 1  is glycine, alanine, valine, leucine, isoleucine, serine, threonine, aspartic acid, glutamic acid, lysine, hydroxylysine, histidine, arginine or α-hydroxymethylserine, 
 Xaa 2  is glycine, alanine, valine, leucine, isoleucine, threonine, serine, asparagine, glutamine, methionine, lysine, hydroxylysine, histidine, arginine or α-hydroxymethylserine, and 
 Xaa 3 , when present, is alanine, aspartic acid, histidine or lysine. 
 
     
     
         503 . The peptide of  claim 502  wherein:
 Xaa 1  is alanine, serine, threonine, lysine, histidine, aspartic acid or glutamic acid, and 
 Xaa 2  is glycine, alanine, valine, leucine, isoleucine, threonine, serine or histidine. 
 
     
     
         504 . The peptide of  claim 503  wherein Xaa 1  is aspartic acid or glutamic acid and Xaa 2  is glycine, alanine, valine, leucine or isoleucine. 
     
     
         505 . The peptide of  claim 504  wherein P 1  is Asp Ala His or Asp Ala His Lys [SEQ ID NO:1]. 
     
     
         506 . The peptide of  claim 503  wherein P 1  is Ser Gly His, Thr Leu His, His Ala His or Ala Ala His. 
     
     
         507 . The peptide of  claim 503  wherein P 1  is Lys His His Lys [SEQ ID NO:11], Asp His His Ala [SEQ ID NO:12], Asp His His Asp [SEQ ID NO:15], His Ala His Ala [SEQ ID NO:13], Ala His His Ala [SEQ ID NO:14] or Ala Ala His His [SEQ ID NO:16]. 
     
     
         508 . The peptide of any one of  claims 501 - 507  wherein the sequence of the Cu(I) binding site of P 2  is one of the following sequences: 
       
         
           
                 
                 
                 
               
                     
                   Met Xaa 4  Met, 
                     
                 
                     
                     
                 
                     
                   Met Xaa 4  Xaa 4  Met, 
                     
                 
                     
                     
                 
                     
                   Cys Cys, 
                     
                 
                     
                     
                 
                     
                   Cys Xaa 4  Cys, 
                     
                 
                     
                     
                 
                     
                   Cys Xaa 4  Xaa 4  Cys, 
                     
                 
                     
                     
                 
                     
                   Met Xaa 4  Cys Xaa 4  Xaa 4  Cys, 
                     
                 
                     
                     
                 
                     
                   Gly Met Xaa 4  Cys Xaa 4  Xaa 4  Cys, 
                   [SEQ ID NO: 7] 
                 
                     
                     
                 
                     
                   Gly Met Thr Cys Xaa 4  Xaa 4  Cys, 
                   [SEQ ID NO: 8] 
                 
                     
                     
                 
                     
                   Gly Met Thr Cys Ala Asn Cys, 
                   [SEQ ID NO: 9] 
                 
                     
                   or 
                     
                 
                     
                     
                 
                     
                   γ-Glu Cys Gly, 
                     
                 
             
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
               
            
           
         
       
       wherein Xaa 4  is any amino acid. 
     
     
         509 . The peptide of  claim 501 ,  505  or  507  wherein the sequence of the Cu(I) binding site of P 2  is Met Xaa 4  Met, wherein Xaa 4  is any amino acid. 
     
     
         510 . The peptide of  claim 501 ,  505  or  507  wherein the sequence of the Cu(I) binding site of P 2  is Met Xaa 4  Xaa 4  Met, wherein Xaa 4  is any amino acid. 
     
     
         511 . The peptide of  claim 501 ,  505  or  507  wherein the sequence of the Cu(I) binding site of P 2  is Cys Cys. 
     
     
         512 . The peptide of  claim 501 ,  505  or  507  wherein the sequence of the Cu(I) binding site of P 2  is Cys Xaa 4  Cys, wherein Xaa 4  is any amino acid. 
     
     
         513 . The peptide of  claim 501 ,  505  or  507  wherein the sequence of the Cu(I) binding site of P 2  is Cys Xaa 4  Xaa 4  Cys, wherein Xaa 4  is any amino acid. 
     
     
         514 . The peptide of  claim 501 ,  505  or  507  wherein the sequence of the Cu(I) binding site of P 2  is Met Xaa 4  Cys Xaa 4  Xaa 4  Cys, wherein Xaa 4  is any amino acid. 
     
     
         515 . The peptide of  claim 501 ,  505  or  507  wherein the sequence of the Cu(I) binding site of P 2  is Gly Met Xaa 4  Cys Xaa 4  Xaa 4  Cys [SEQ ID NO:7], wherein Xaa 4  is any amino acid. 
     
     
         516 . The peptide of  claim 501 ,  505  or  507  wherein the sequence of the Cu(I) binding site of P 2  is Gly Met Thr Cys Xaa 4  Xaa 4  Cys [SEQ ID NO:8], wherein Xaa 4  is any amino acid. 
     
     
         517 . The peptide of  claim 501 ,  505  or  507  wherein the sequence of the Cu(I) binding site of P 2  is Gly Met Thr Cys Ala Asn Cys [SEQ ID NO:9]. 
     
     
         518 . The peptide of  claim 505  wherein the sequence of P 2  is Gly Met Thr Cys Ala Asn Cys [SEQ ID NO:9]. 
     
     
         519 . The peptide of  claim 501 ,  505  or  507  wherein the sequence of the Cu(I) binding site of P 2  is γ-Glu Cys Gly. 
     
     
         520 . The peptide of  claim 501  wherein at least one amino acid of P 1  other than β-alanine or glycine, when present, is a D-amino acid. 
     
     
         521 . The peptide of  claim 520  wherein all of the amino acids of P 1  other than β-alanine or glycine, when present, are D-amino acids. 
     
     
         522 . The peptide of  claim 501  wherein at least one amino acid of P 2  other than β-alanine or glycine, when present, is a D-amino acid. 
     
     
         523 . The peptide of  claim 520  wherein at least one of the amino acids of P 2  other than β-alanine or glycine, when present, is a D-amino acid. 
     
     
         524 . The peptide of  claim 501  wherein the terminal —COOH of the peptide is substituted to produce —COR 2 , wherein R 2  is —NH 2 , —NHR 1 , —N(R 1 ) 2 , —OR 1  or —R 1 , wherein R 1  is an alkyl, aryl or heteroaryl.