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 pharmaceutical composition comprising a pharmaceutically-acceptable carrier and a linear metal-binding peptide which does not have a metal ion bound to it, 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 ;
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.
2. The composition 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,
Xaa 2 is glycine, alanine, valine, leucine, isoleucine, threonine, senile, asparagine, glutamine, methionine, lysine, hydroxylysine, histidine, arginine or α-hydroxymethylserine, and
Xaa 3 , when present, is alanine, aspartic acid, histidine or lysine.
3. The composition of claim 2 wherein:
Xaa 1 is alanine, serine, threonine, lysine, histidine, aspartic acid or glutamic acid, and
Xaa 2 is glycine, alanine, valine, leucine, isoleucine, threonine, senine or histidine.
4. The composition of claim 3 wherein Xaa 1 is aspartic acid or glutamic acid and Xaa 2 is glycine, alanine, valine, leucine or isoleucine.
5. The composition of claim 4 wherein P 1 is Asp Ala His.
6. The composition of claim 4 wherein P 1 is Asp Ala His Lys[SEQ ID NO:1].
7. The composition of claim 3 wherein P 1 is Ser Gly His, Thr Leu His, His Ala His or Ala Ala His.
8. The composition of claim 3 wherein P 1 is Lys His His Lys [SEQ ID NO:11], Asp His His Ala [SEQ ID NO:12] or Asp His His Asp [SEQ ID NO:15].
9. The composition of claim 3 wherein P 1 is 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].
10. The composition of any one of claims 1 - 9 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, or
[SEQ ID NO:9]
γ-Glu Cys Gly,
wherein Xaa 4 is any amino acid.
11. The composition of claim 10 wherein the sequence of the Cu(I) binding site of P 2 is Met Xaa 4 Met, wherein Xaa 4 is defined in claim 10 .
12. The composition of claim 10 wherein the sequence of the Cu(I) binding site of P 2 is Met Xaa 4 Xaa 4 Met, wherein Xaa 4 is defined in claim 10 .
13. The composition of claim 10 wherein the sequence of the Cu(I) binding site of P 2 is Cys Cys.
14. The composition of claim 10 wherein the sequence of the Cu(I) binding site of P 2 is Cys Xaa 4 Cys, wherein Xaa 4 is defined in claim 10 .
15. The composition of claim 10 wherein the sequence of the Cu(I) binding site of P 2 is Cys Xaa 4 Xaa 4 Cys, wherein Xaa 4 is defined in claim 10 .
16. The composition of claim 10 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 defined in claim 10 .
17. The composition of claim 10 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 defined in claim 10 .
18. The composition of claim 10 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 defined in claim 10 .
19. The composition of claim 10 wherein the sequence of the Cu(I) binding site of P 2 is Gly Met Thr Cys Ala Asn Cys [SEQ ID NO:9].
20. The composition of claim 5 wherein the sequence of P 2 is Gly Met Thr Cys Ala Asn Cys [SEQ ID NO:9].
21. The composition of claim 6 wherein the sequence of P 2 is Gly Met Thr Cys Ala Asn Cys [SEQ ID NO:9].
22. The composition of claim 10 wherein the sequence of the Cu(I) binding site of P 2 is γ-Glu Cys Gly.
23. The composition of claim 1 wherein at least one amino acid of P 1 other than β-alanine or glycine, when present, is a D-amino acid.
24. The composition of claim 23 wherein all of the amino acids of P 1 other than β-alanine or glycine, when present, are D-amino acids.
25. The composition of claim 1 wherein at least one amino acid of P 2 other than β-alanine or glycine, when present, is a D-amino acid.
26. The composition of claim 23 wherein at least one of the amino acids of P 2 other than β-alanine or glycine, when present, is a D-amino acid.
27. The composition of claim 1 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.