Use of ADNF polypeptides for treating peripheral neurotoxicity
View Patent ↗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 the treatment of cancer or neoplasia with reduced peripheral neurotoxicity, the method comprising
a) administering an anti-cancer agent to a subject in need thereof; and
b) administering, contemporaneously or sequentially with the anti-cancer agent of step a), an ADNF polypeptide in an effective amount in a pharmaceutically acceptable carrier, thereby reducing peripheral neurotoxicity associated with the anti-cancer agent, wherein the ADNF polypeptide is a member selected from the group consisting of:
(i) an ADNF I polypeptide comprising an active core site having the amino acid sequence of Ser-Ala-Leu-Leu-Arg-Ser-Ile-Pro-Ala (SEQ ID NO:1), wherein at least one amino acid in SEQ ID NO:1 is optionally a D-amino acid;
(ii) an ADNF III polypeptide comprising an active core site having the amino acid sequence of Asn-Ala-Pro-Val-Ser-Ile-Pro-Gln (SEQ ID NO:2), wherein at least one amino acid in SEQ ID NO:2 is optionally a D-amino acid; and
(iii) a mixture of the ADNF I polypeptide of part (i) and the ADNF III polypeptide of part (ii).
2. The method of claim 1 , wherein said anti-cancer agent is a vinca alkaloid.
3. 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.
4. The method of claim 1 , wherein the ADNF polypeptide is an ADNF I polypeptide of part (i).
5. The method of claim 1 , wherein the active core site of the ADNF polypeptide comprises at least one D-amino acid.
6. 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.
7. The method of claim 6 , wherein the ADNF I polypeptide is Ser-Ala-Leu-Leu-Arg-Ser-Ile-Pro-Ala (SEQ ID NO:1).
8. The method of claim 6 , wherein the ADNF I polypeptide is selected from the group consisting of:
(SEQ ID NO: 3)
Val-Leu-Gly-Gly-Gly-Ser-Ala-Leu-Leu-Arg-Ser-Ile-
Pro-Ala;
(SEQ ID NO: 4)
Val-Glu-Glu-Gly-Ile-Val-Leu-Gly-Gly-Gly-Ser-Ala-
Leu-Leu-Arg-Ser-Ile-Pro-Ala;
(SEQ ID NO: 5)
Leu-Gly-Gly-Gly-Ser-Ala-Leu-Leu-Arg-Ser-Ile-Pro-
Ala;
(SEQ ID NO: 6)
Gly-Gly-Gly-Ser-Ala-Leu-Leu-Arg-Ser-Ile-Pro-Ala;
(SEQ ID NO: 7)
Gly-Gly-Ser-Ala-Leu-Leu-Arg-Ser-Ile-Pro-Ala;
(SEQ ID NO: 8)
Gly-Ser-Ala-Leu-Leu-Arg-Ser-Ile-Pro-Ala;
and
(SEQ ID NO: 1)
Ser-Ala-Leu-Leu-Arg-Ser-Ile-Pro-Ala.
9. The method of claim 6 , 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.
10. The method of claim 1 , wherein the ADNF polypeptide is an ADNF III polypeptide of part (ii).
11. The method of claim 10 , 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.
12. The method of claim 10 , wherein the ADNF III polypeptide is Asn-Ala-Pro-Val-Ser-Ile-Pro-Gln (SEQ ID NO:2).
13. The method of claim 10 , wherein the active core site of the ADNF III polypeptide comprises at least one D-amino acid.
14. The method of claim 10 , wherein the ADNF III polypeptide is a member selected from the group consisting of:
(SEQ ID NO: 9)
Gly-Gly-Asn-Ala-Pro-Val-Ser-Ile-Pro-Gln;
(SEQ ID NO: 10)
Leu-Gly-Gly-Asn-Ala-Pro-Val-Ser-Ile-Pro-Gln-Gln-
Ser;
(SEQ ID NO: 11)
Leu-Gly-Leu-Gly-Gly-Asn-Ala-Pro-Val-Ser-Ile-Pro-
Gln-Gln-Ser;
(SEQ ID NO: 12)
Ser-Val-Arg-Leu-Gly-Leu-Gly-Gly-Asn-Ala-Pro-Val-
Ser-Ile-Pro-Gln-Gln-Ser;
and
(SEQ ID NO: 2)
Asn-Ala-Pro-Val-Ser-Ile-Pro-Gln.
15. The method of claim 10 , 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.
16. The method of claim 1 , wherein a mixture of the ADNF I polypeptide of part (i) and the ADNF III polypeptide of part (ii) is administered to the subject.
17. The method of claim 16 , wherein either or both active core sites of the ADNF I polypeptide and the ADNF III polypeptide comprise at least one D-amino acid.
18. The method of claim 16 , 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).
19. The method of claim 16 , wherein the ADNF I polypeptide is a member selected from the group consisting of:
(SEQ ID NO : 3)
Val-Leu-Gly-Gly-Gly-Ser-Ala-Leu-Leu-Arg-Ser-Ile-
Pro-Ala;
(SEQ ID NO: 4)
Val-Glu-Glu-Gly-Ile-Val-Leu-Gly-Gly-Gly-Ser-Ala-
Leu-Leu-Arg-Ser-Ile-Pro-Ala;
(SEQ ID NO: 5)
Leu-Gly-Gly-Gly-Ser-Ala-Leu-Leu-Arg-Ser-Ile-Pro-
Ala;
(SEQ ID NO: 6)
Gly-Gly-Gly-Ser-Ala-Leu-Leu-Arg-Ser-Ile-Pro-Ala;
(SEQ ID NO: 7)
Gly-Gly-Ser-Ala-Leu-Leu-Arg-Ser-Ile-Pro-Ala;
(SEQ ID NO: 8)
Gly-Ser-Ala-Leu-Leu-Arg-Ser-Ile-Pro-Ala;
and
(SEQ ID NO: 1)
Ser-Ala-Leu-Leu-Arg-Ser-Ile-Pro-Ala;
and
wherein the ADNF III polypeptide is selected from
the group consisting of:
(SEQ ID NO: 9)
Gly-Gly-Asn-Ala-Pro-Val-Ser-Ile-Pro-Gln;
(SEQ ID NO: 10)
Leu-Gly-Gly-Asn-Ala-Pro-Val-Ser-Ile-Pro-Gln-Gln-
Ser;
(SEQ ID NO: 11)
Leu-Gly-Leu-Gly-Gly-Asn-Ala-Pro-Val-Ser-Ile-Pro-
Gln-Gln-Ser;
(SEQ ID NO: 12)
Ser-Val-Arg-Leu-Gly-Leu-Gly-Gly-Asn-Ala-Pro-Val-
Ser-Ile-Pro-Gln-Gln-Ser;
and
(SEQ ID NO: 2)
Asn-Ala-Pro-Val-Ser-Ile-Pro-Gln.
20. The method of claim 16 , 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.
21. The method of claim 1 , wherein the ADNF polypeptide is administered intranasally, orally, intravenously or subcutaneously.