Peptide fragments of netrin-1 and compositions and methods thereof

1. A peptide consisting of 8-35 amino acid residues and having a core sequence represented by Formula IA as follows:

C-X1-X2-C-X3-X4-X5-X6-T-X7-G (SEQ ID NO: 11)  (IA)

wherein

X1 may be present or absent, and if present, X1 is selected from the group consisting of A, V, L, I, P, F, M, and W;

X2 may be present or absent, and if present, X2 is selected from the group consisting of D, E, G, N, Q, S, T, Y, and C;

X3 is selected from the group consisting of K, R, and H;

X4 is selected from the group consisting of D, E, K, R, H, Y, F, and W;

X5 is selected from the group consisting of G, N, Q, S, T, Y, and C;

X6 may be present or absent and if present, X6 is selected from the group consisting of T, V, and I; and

X7 may be present or absent, and if present, X7 is selected from the group consisting of A, V, L, I, P, F, M, and W; and

wherein either X1, X2, or both X1 and X2 are present; wherein the peptide has improved efficacy in reducing ischemia/reperfusion injury or reducing infarct size as compared to netrin-1.

2. The peptide according to claim 1 wherein the core sequence is represented by Formula IB as follows:

C-X1-X2-C-R-H-N-T-A-G (SEQ ID NO: 12)  (IB)

wherein

X1 may be present or absent, and if present, X1 is selected from the group consisting of A, V, L, I, P, F, M, and W; and

X2 may be present or absent, and if present, X2 is selected from the group consisting of D, E, G, N, Q, S, T, Y, and C; and

wherein either X1, X2, or both X1 and X2 are present.

3. The peptide according to claim 2 , wherein at least one amino acid residue is different from the corresponding amino acid residue of a naturally occurring netrin-1 protein sequence.

4. The peptide according to claim 3 , wherein the peptide is about 8-30, about 8-20, about 8-15, about 8-12, 8-11, about 9-30, about 9-20, about 9-15, about 9-12, or 9-11 amino acid residues long.

5. The peptide according to claim 4 , wherein the peptide is 8, 9, 10, or 11 amino acid residues long.

6. The peptide according to claim 1 , wherein the peptide is about 8-30, about 8-20, about 8-15, about 8-12, 8-11, about 9-30, about 9-20, about 9-15, about 9-12, or 9-11 amino acid residues long.

7. The peptide according to claim 1 , wherein the peptide is 8, 9, 10, or 11 amino acid residues long.

8. The peptide according to claim 1 , wherein at least one amino acid residue is different from the corresponding amino acid residue of a naturally occurring netrin-1 protein sequence.

9. The peptide according to claim 1 , wherein the amino acid sequence is SEQ ID NO: 4, SEQ ID NO: 5, SEQ ID NO: 6, SEQ ID NO: 7, or SEQ ID NO: 8.

10. A composition comprising a first peptide and a second peptide,

wherein the first and second peptides each independently consist of 8-35 amino acid residues and having a core sequence represented by Formula IA as follows:

C-X1-X2-C-X3-X4-X5-X6-T-X7-G (SEQ ID NO: 11)  (IA)

wherein

X1 may be present or absent, and if present, X1 is selected from the group consisting of A, V, L, I, P, F, M, and W;

X2 may be present or absent, and if present, X2 is selected from the group consisting of D, E, G, N, Q, S, T, Y, and C;

X3 is selected from the group consisting of K, R, and H;

X4 is selected from the group consisting of D, E, K, R, H, Y, F, and W;

X5 is selected from the group consisting of G, N, Q, S, T, Y, and C;

X6 may be present or absent and if present, X6 is selected from the group consisting of T, V, and I; and

X7 may be present or absent, and if present, X7 is selected from the group consisting of A, V, L, I, P, F, M, and W; and

wherein either X1, X2, or both X1 and X2 are present, and

wherein the first peptide contains a core sequence according to Formula IA wherein X1 is absent, and the second peptide contains a core sequence according to Formula IA wherein X1 and X2 are present.

11. A method of stimulating, increasing, or enhancing nitric oxide production by, or phosphorylation of ERK1/2 and/or eNOS in endothelial cells, which comprises administering to the endothelial cells one or more peptides consisting of 8-35 amino acid residues and having a core sequence represented by Formula IA as follows:

C-X1-X2-C-X3-X4-X5-X6-T-X7-G (SEQ ID NO: 11)  (IA)

wherein

X1 may be present or absent, and if present, X1 is selected from the group consisting of A, V, L, I, P, F, M, and W;

X2 may be present or absent, and if present, X2 is selected from the group consisting of D, E, G, N, Q, S, T, Y, and C;

X3 is selected from the group consisting of K, R, and H;

X4 is selected from the group consisting of D, E, K, R, H, Y, F, and W;

X5 is selected from the group consisting of G, N, Q, S, T, Y, and C;

X6 may be present or absent and if present, X6 is selected from the group consisting of T, V, and I; and

X7 may be present or absent, and if present, X7 is selected from the group consisting of A, V, L, I, P, F, M, and W; and

wherein either X1, X2, or both X1 and X2 are present.

12. A method of treating, inhibiting, or reducing an injury to a cardiac tissue or a heart, wherein the injury is caused by superoxides, ischemia/reperfusion, or myocardial infarction, which comprises stimulating, increasing, or enhancing nitric oxide production by endothelial cells in the cardiac tissue or the heart and/or stimulating or inducing phosphorylation of ERK1/2, eNOS, or both in the endothelial cells by administering to the endothelial cells, before, during, and/or after the injury, one or more peptides consisting of 8-35 amino acid residues and having a core sequence represented by Formula IA as follows:

C-X1-X2-C-X3-X4-X5-X6-T-X7-G (SEQ ID NO: 11)  (IA)

wherein

X1 may be present or absent, and if present, X1 is selected from the group consisting of A, V, L, I, P, F, M, and W;

X2 may be present or absent, and if present, X2 is selected from the group consisting of D, E, G, N, Q, S, T, Y, and C;

X3 is selected from the group consisting of K, R, and H;

X4 is selected from the group consisting of D, E, K, R, H, Y, F, and W;

X5 is selected from the group consisting of G, N, Q, S, T, Y, and C;

X6 may be present or absent and if present, X6 is selected from the group consisting of T, V, and I; and

X7 may be present or absent, and if present, X7 is selected from the group consisting of A, V, L, I, P, F, M, and W; and

wherein either X1, X2, or both X1 and X2 are present.

13. The method of claim 12 , wherein the injury is caused by myocardial infarction and the administration reduces the infarct size of the heart.

14. The method of claim 12 , wherein the injury is an ischemia/reperfusion injury.

15. The method according to claim 14 , wherein the infarct size of the heart is decreased or reduced.

16. The method according to claim 15 , wherein the therapeutically effective amount is 0.001 to 100 mg/kg of the subject.

17. The method according to claim 14 , wherein the therapeutically effective amount is 0.001 to 100 mg/kg of the subject.