Metal-binding compounds and uses therefor
View Patent ↗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. A method of treating inflammation in an animal in need thereof comprising administering to the animal an effective amount of a metal-binding peptide which does not have a metal ion bound to it or of a physiologically-acceptable salt of the peptide, the sequence of the peptide being:
P 1 -P 2 ,
wherein:
P 1 is:
Xaa 1 Xaa 2 His or
Xaa 1 Xaa 2 His Xaa 3 ,
the P 1 portion of the peptide being linear;
Xaa 1 is the N-terminal amino acid of the peptide, the only substituents on the α-amino group of Xaa 1 are hydrogen, and Xaa 1 is glycine, 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;
Xaa 2 is 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;
Xaa 3 is glycine, alanine, valine, lysine, arginine, ornithine, aspartic acid, glutamic acid, asparagine, glutamine or tryptophan; and
P 2 is an amino acid sequence which comprises the sequence of a Cu(I) binding site, and P 2 contains no more than 10 amino acids.
2. The method of claim 1 wherein:
Xaa 1 is glycine, alanine, valine, leucine, isoleucine, serine, threonine, aspartic acid, glutamic acid, lysine, hydroxylysine, histidine, arginine, or α-hydroxymethylserine, and
Xaa 2 is alanine, valine, leucine, isoleucine, threonine, serine, asparagine, glutamine, cysteine, methionine, lysine, hydroxylysine, histidine, arginine, or α-hydroxymethylserine.
3. The method of claim 1 wherein Xaa 1 is aspartic acid, glutamic acid, arginine, threonine or α-hydroxymethylserine.
4. The method of claim 1 wherein Xaa 2 is alanine, valine, leucine, isoleucine, threonine, serine, asparagine, methionine, histidine or α-hydroxymethylserine.
5. The method of claim 1 wherein Xaa 3 is lysine.
6. The method of claim 1 wherein:
Xaa 1 is aspartic acid, glutamic acid, arginine, lysine, threonine, serine or α-hydroxymethylserine,
Xaa 2 is alanine, valine, leucine, isoleucine, threonine, serine, asparagine, methionine, histidine or α-hydroxymethylserine, and
Xaa 3 , when present, is lysine.
7. The method of claim 6 wherein Xaa 1 is aspartic acid or glutamic acid and Xaa 2 is alanine, valine, leucine, isoleucine, threonine, serine or α-hydroxymethylserine.
8. The method of claim 7 wherein Xaa 2 is alanine, valine, leucine or isoleucine.
9. The method of claim 8 wherein P 1 is Asp Ala His or Asp Ala His Lys.
10. The method of claim 9 wherein P 1 is Asp Ala His Lys.
11. The method of claim 6 wherein Xaa 1 is arginine, lysine, threonine, serine or α-hydroxymethylserine, and Xaa 2 is alanine, valine, leucine, isoleucine, threonine, serine or α-hydroxymethylserine.
12. The method of claim 11 wherein P 1 is Thr Leu His, HMS HMS His or Arg Thr His.
13. The method of claim 1 wherein P 2 comprises 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.
14. The method of claim 13 wherein P 2 is Gly Met Thr Cys Ala Asn Cys [SEQ ID NO:9].
15. The method of claim 1 wherein at least one of the amino acids of P 1 other than β-alanine or glycine, when present, is a D-amino acid.
16. The method of claim 1 wherein at least one of the amino acids of P 2 other than β-alanine or glycine, when present, is a D-amino acid.
17. The method of claim 15 wherein at least one of the amino acids of P 2 other than β-alanine or glycine, when present, is a D-amino acid.
18. The method of claim 1 wherein the terminal —COOH of P 1 -P 2 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.
19. The method of claim 13 wherein P 1 is Asp Ala His or Asp Ala His Lys.
20. The method of claim 14 wherein P 1 is Asp Ala His or Asp Ala His Lys.