Use of ADNF polypeptides for treating peripheral neurotoxicity
This invention relates to the use of ADNF polypeptides in the treatment of neurotoxicity induced by chemical agents or by disease processes. The ADNF polypeptides include ADNF I and ADNF III (also referred to as ADNP) polypeptides, analogs, subsequences such as NAP and SAL, and D-amino acid versions (either wholly D-amino acid peptides or mixed D- and L-amino acid peptides), and combinations thereof which contain their respective active core sites.
1. A method for treating peripheral neurotoxicity in a subject, the method comprising administering a therapeutically effective amount of an ADNF polypeptide to a subject in need thereof, wherein the ADNF polypeptide is a member selected from the group consisting of:
(a) an ADNF I polypeptide comprising an active core site having the following amino acid sequence:
Ser-Ala-Leu-Leu-Arg-Ser-Ile-Pro-Ala (SEQ ID NO:1);
(b) an ADNF III polypeptide comprising an active core site having the following amino acid sequence:
Asn-Ala-Pro-Val-Ser-Ile-Pro-Gln (SEQ ID NO:2), and
(c) a mixture of the ADNF I polypeptide of part (a) and the ADNF III polypeptide of part (b);
wherein said peripheral neurotoxicity is a consequence of treatment with one or more chemical agents.
2. The method of claim 1 , wherein the ADNF polypeptide is a member selected from the group consisting of a full length ADNF I polypeptide, a full length ADNF III polypeptide (ADNP), and a mixture of a full length ADNF I polypeptide and a full length ADNF III polypeptide.
3. The method of claim 1 , wherein the ADNF polypeptide is an ADNF I polypeptide.
4. The method of claim 1 , wherein the active core site of the ADNF polypeptide comprises at least one D-amino acid.
5. The method of claim 1 , wherein the ADNF I polypeptide has the formula (R 1 ) x -Ser-Ala-Leu-Leu-Arg-Ser-Ile-Pro-Ala-(R 2 ) y (SEQ ID NO:20), in which
R 1 is an amino acid sequence comprising from 1 to about 40 amino acids wherein each amino acid is independently selected from the group consisting of naturally occurring amino acids and amino acid analogs;
R 2 is an amino acid sequence comprising from 1 to about 40 amino acids wherein each amino acid is independently selected from the group consisting of naturally occurring amino acids and amino acid analogs; and
x and y are independently selected and are equal to zero or one and at least one of them is equal to one.
6. The method of claim 1 , wherein the ADNF I polypeptide is Ser-Ala-Leu-Leu-Arg-Ser-Ile-Pro-Ala (SEQ ID NO:1).
7. The method of claim 1 , wherein the ADNF I polypeptide is selected from the group consisting of:
Val-Leu-Gly-Gly-Gly-Ser-Ala-Leu-Leu-
(SEQ ID NO:3)
Arg-Ser-Ile-Pro-Ala;
Val-Glu-Glu-Gly-Ile-Val-Leu-Gly-Gly-
(SEQ ID NO:4)
Gly-Ser-Ala-Leu-Leu-Arg-Ser-Ile-Pro-
Ala;
Leu-Gly-Gly-Gly-Ser-Ala-Leu-Leu-Arg-
(SEQ ID NO:5)
Ser-Ile-Pro-Ala;
Gly-Gly-Gly-Ser-Ala-Leu-Leu-Arg-Ser-
(SEQ ID NO:6)
Ile-Pro-Ala;
Gly-Gly-Ser-Ala-Leu-Leu-Arg-Ser-Ile-
(SEQ ID NO:7)
Pro-Ala;
Gly-Ser-Ala-Leu-Leu-Arg-Ser-Ile-Pro-
(SEQ ID NO:8)
Ala;
and
Ser-Ala-Leu-Leu-Arg-Ser-Ile-Pro-Ala.
(SEQ ID NO:1)
8. The method of claim 1 , wherein the ADNF I polypeptide comprises up to about 20 amino acids at either or both of the N-terminus and the C-terminus of the active core site.
9. The method of claim 1 , wherein the ADNF polypeptide is an ADNF III polypeptide.
10. The method of claim 9 , wherein the ADNF III polypeptide has the formula (R 1 ) x -Asn-Ala-Pro-Val-Ser-Ile-Pro-Gln-(R 2 ) y (SEQ ID NO:13), in which
R 1 is an amino acid sequence comprising from 1 to about 40 amino acids wherein each amino acid is independently selected from the group consisting of naturally occurring amino acids and amino acid analogs;
R 2 is an amino acid sequence comprising from 1 to about 40 amino acids wherein each amino acid is independently selected from the group consisting of naturally occurring amino acids and amino acid analogs; and
x and y are independently selected and are equal to zero or one.
11. The method of claim 9 , wherein the ADNF III polypeptide is Asn-Ala-Pro-Val-Ser-Ile-Pro-Gln (SEQ ID NO:2).
12. The method of claim 9 , wherein the active core site of the ADNF III polypeptide comprises at least one D-amino acid.
13. The method of claim 9 , wherein the ADNF III polypeptide is a member selected from the group consisting of:
Gly-Gly-Asn-Ala-Pro-Val-Ser-Ile-Pro-
(SEQ ID NO:9)
Gln;
Leu-Gly-Gly-Asn-Ala-Pro-Val-Ser-Ile-
(SEQ ID NO:10)
Pro-Gln-Gln-Ser;
Leu-Gly-Leu-Gly-Gly-Asn-Ala-Pro-Val-
(SEQ ID NO:11)
Ser-Ile-Pro-Gln-Gln-Ser;
Ser-Val-Arg-Leu-Gly-Leu-Gly-Gly-Asn-
(SEQ ID NO:12)
Ala-Pro-Val-Ser-Ile-Pro-Gln-Gln-Ser;
and
Asn-Ala-Pro-Val-Ser-Ile-Pro-Gln.
(SEQ ID NO:2)
14. The method of claim 9 , wherein the ADNF III polypeptide comprises up to about 20 amino acids at either or both of the N-terminus and the C-terminus of the active core site.
15. The method of claim 1 , wherein a mixture of the ADNF I polypeptide of part (a) and the ADNF III polypeptide of part (b) are administered to the subject.
16. The method of claim 15 , wherein either or both active core sites of the ADNF I polypeptide and the ADNF III polypeptide comprise at least one D-amino acid.
17. The method of claim 15 , wherein the ADNF I polypeptide is Ser-Ala-Leu-Leu-Arg-Ser-Ile-Pro-Ala (SEQ ID NO:1), and wherein the ADNF III polypeptide is Asn-Ala-Pro-Val-Ser-Ile-Pro-Gln (SEQ ID NO:2).
18. The method of claim 15 , wherein the ADNF I polypeptide is a member selected from the group consisting of:
Val-Leu-Gly-Gly-Gly-Ser-Ala-Leu-Leu-
(SEQ ID NO:3)
Arg-Ser-Ile-Pro-Ala;
Val-Glu-Glu-Gly-Ile-Val-Leu-Gly-Gly-
(SEQ ID NO:4)
Gly-Ser-Ala-Leu-Leu-Arg-Ser-Ile-Pro-
Ala;
Leu-Gly-Gly-Gly-Ser-Ala-Leu-Leu-Arg-
(SEQ ID NO:5)
Ser-Ile-Pro-Ala;
Gly-Gly-Gly-Ser-Ala-Leu-Leu-Arg-Ser-
(SEQ ID NO:6)
Ile-Pro-Ala;
Gly-Gly-Ser-Ala-Leu-Leu-Arg-Ser-Ile-
(SEQ ID NO:7)
Pro-Ala;
Gly-Ser-Ala-Leu-Leu-Arg-Ser-Ile-Pro-
(SEQ ID NO:8)
Ala;
and
Ser-Ala-Leu-Leu-Arg-Ser-Ile-Pro-Ala;
(SEQ ID NO:1)
and
wherein the ADNF III polypeptide is selected from the group consisting of:
Gly-Gly-Asn-Ala-Pro-Val-Ser-Ile-Pro-
(SEQ ID NO:9)
Gln;
Leu-Gly-Gly-Asn-Ala-Pro-Val-Ser-Ile-
(SEQ ID NO:10)
Pro-Gln-Gln-Ser;
Leu-Gly-Leu-Gly-Gly-Asn-Ala-Pro-Val-
(SEQ ID NO:11)
Ser-Ile-Pro-Gln-Gln-Ser;
Ser-Val-Arg-Leu-Gly-Leu-Gly-Gly-Asn-
(SEQ ID NO:12)
Ala-Pro-Val-Ser-Ile-Pro-Gln-Gln-Ser;
and
Asn-Ala-Pro-Val-Ser-Ile-Pro-Gln.
(SEQ ID NO:2)
19. The method of claim 15 , wherein the ADNF I polypeptide comprises up to about 20 amino acids at either or both of the N-terminus and the C-terminus of the active core site of the ADNF I polypeptide, and wherein the ADNF III polypeptide comprises up to about 20 amino acids at either or both of the N-terminus and the C-terminus of the active core site of the ADNF III polypeptide.
20. The method of claim 1 , wherein the ADNF polypeptide is administered intranasally, orally, intravenously or subcutaneously.
21. The method of claim 1 , wherein said one or more chemical agent is selected from among chemical agents for cancer, multiple sclerosis, gout, arthritis, Behcet's disease, psychiatric disorder, immunosuppression and infectious disease.
22. The method of claim 1 , wherein said one or more chemical agent is selected from the group consisting of vinca alkaloids, platinum drugs, L-asparaginase, taxanes, thalidomide, methotrexate, colchicines, and anti-infective agents.
23. The method of claim 21 , wherein said one or more chemical agent is a chemical agent for cancer.
24. The method of claim 22 , wherein said one or more chemical agent is selected from the group consisting of: vinca alkaloids and taxanes.