Modified pigment epithelium-derived factor (PEDF) peptides and uses thereof for treating neovascular diseases, inflammatory diseases, cancer, and for cytoprotection

1. A modified peptide comprising an N-terminal carboxyl group and a modified amino acid sequence as follows:

Z-B-X-AA0-AA1-AA2-AA3-AA4-AA5-AA6-AA7-AA8-AA9-AA10-Y  (SEQ ID NO:14)

wherein:

AA0 is absent or present, and when AA0 is present AA0 is selected from the group consisting of sarcosyl, and Gly;

AA1 is absent or present, and when AA1 is present AA1 is selected from the group consisting of sarcosyl and Gly;

AA2 is Tyr;

AA3 is Asp or Asn;

AA4 is Leu, Ile, or Val;

AA5 is Tyr or Phe;

AA6 is Arg;

AA7 is Val or Pro;

AA8 is present or absent, and when AA8 is present AA8 is selected from the group consisting of Arg, Pro, and Gln;

AA9 is present or absent, and when AA9 is present AA9 is selected from the group consisting of Ser and Ala;

AA10 is absent or present and when AA10 is present AA10 is selected from the group consisting of Ser, and Ser-Thr,

X is absent or present, and when X is present X is selected from the group consisting of acetyl, butyryl, hexanoyl, methoxy-PEG (n) CO, hydroxy-PEG (n) CO, amino-PEG (n) CO, and sarcosyl-amino-PEG (n) CO, where n is 3-13, and X is in an amide bond to an amino terminus of AA0, AA1, or AA2;

B is absent or present, and when B is present B is a di-carboxylic acid containing from 4-8 carbon atoms, which may be straight-chain or branched, and B is in a half-amide bond to an amino terminus of X, or B is in a half-amide bond to an amino terminus of AA0 when X is absent, or B is in a half-amide bond to an amino terminus of AA1 when X and AA0 are absent, or B is in a half-amide bond to an amino terminus of AA2 when X, AA0 and AA1 are absent; and B may end in a free carboxyl group, or this otherwise free carboxyl group may be in an ester bond to a hydroxyl group of Z;

wherein if B is present X is absent, and wherein if X is present B is absent;

Z is absent or present if B is present, Z is absent if X is present, and when Z is present Z is joined through an ester bond to a carbonyl group of B, and Z is selected from the group consisting of: primary or secondary hydroxyl groups of sugar monomers present on a polymeric carbohydrate carrier; hydroxyl groups of a hydroxyl terminal dendrimer; and primary or secondary hydroxyl groups of acyclic or cyclic amino alcohols having between 4 and 6 carbon atoms and a single primary or secondary amine that is protected through an amide bond or a carbamate bond; and

Y is an amide or a substituted amide selected from the group consisting of amide or ethylamide.

2. The modified peptide of claim 1 comprising a modified amino acid sequence as follows:

B-AA0-AA1-AA2-AA3-AA4-AA5-AA6-AA7-AA8-AA9-Y  (SEQ ID NO:14).

3. The modified peptide of claim 1 , wherein B is adipic acid or glutaric acid in half amide bond to AA0, or B is in a half-amide bond to an amino terminus of AA1 when AA0 is absent, or B is in a half-amide bond to an amino terminus of AA2 when AA0 and AA1 are absent.

4. The modified peptide of claim 1 , wherein B is present selected from the group consisting of succinic acid, glutaric acid, adipic acid, and suberic acid.

5. The modified peptide of claim 1 ,

wherein the modified peptide has a modified amino acid sequence selected from:

sarcosyl-AA1-AA2-AA3-AA4-AA5-AA6-AA7-AA8-AA9-Y (SEQ ID NO: 14); and

glutaryl-sarcosyl-AA1-AA2-AA3-AA4-AA5-AA6-AA7-AA8-AA9-amide (SEQ ID NO:14).

6. The modified peptide of claim 5 , wherein the modified peptide has a modified amino acid sequence of:

glutaryl-sarcosyl-Gly-Tyr-AA3-Leu-Tyr-Arg-Val-AA8-AA9-amide (SEQ ID NO:14).

7. The modified peptide of claim 6 , wherein the modified peptide has a modified amino acid sequence selected from:

glutaryl-sarcosyl-Gly-Tyr-Asp-Leu-Tyr-Arg-Val-Arg-Ser-amide (SEQ ID NO:2);

glutaryl-sarcosyl-Gly-Tyr-Asn-Leu-Tyr-Arg-Val-Arg-Ser-amide (SEQ ID NO:4);

glutaryl-sarcosyl-Gly-Tyr-Asn-Leu-Tyr-Arg-Val-Pro-ethylamide (SEQ ID NO:8).

8. The modified peptide of claim 1 ,

wherein the modified peptide has a modified amino acid sequence selected from the group consisting of:

adipoyl-sarcosyl-Tyr-Asn-Leu-Tyr-Arg-Val-Arg-Ser-amide (SEQ ID NO: 11); and

adipoyl-sarcosyl-Tyr-Asn-Leu-Tyr-Arg-Val-Pro-ethylamide (SEQ ID NO:10).

9. The modified peptide of claim 1 , wherein the sequence AA2-AA3-AA4-AA5-AA6 of SEQ ID NO: 14 is Tyr-Asn-Leu-Tyr-Arg (residues 1-5 of SEQ ID NOs: 9-11).

10. A prodrug comprising:

(a) a carrier particle comprising carboxyl groups or hydroxyl groups; and

(b) the modified peptide of claim 1 conjugated to the polymeric carrier particle.

11. A prodrug of claim 10 in which the prodrug further comprises an amino alcohol linker that links the peptide to the carrier particle, the peptide is esterified to a free hydroxyl group of the linker, the linker is attached to the carrier particle via the amino group of the linker and a free hydroxyl group of the carrier particle forming a carbamate bond, or via the amino group of the linker and a free carboxyl group of the carrier particle forming an amide bond.

12. The prodrug of claim 11 , wherein the linker is selected from the group consisting of amino-n-butoxy, amino-ethoxyethyloxy, amino-piperidyl(3, or 4)-oxy, amino-pyrrolidinyl(3)-oxy, amino-benzyloxy, BOC-aminoethylamido-valeric acid (4)-oxy, amino-cyclohexyl (3, or 4)-oxy, and amino-cyclopentyl (3)-oxy.

13. The prodrug of claim 10 , wherein the carrier particle comprises dextrin, dextran, or hyaluronic acid.

14. A pharmaceutical composition comprising the modified peptide of claim 1 or a prodrug thereof and a pharmaceutical carrier.

15. A method of treating and/or preventing cancer in a subject in need thereof, the method comprising administering the pharmaceutical composition of claim 14 to the subject.

16. A method of treating and/or preventing infectious disease in a subject having immune system exhaustion characterized by elevated PD-L1, the method comprising administering the composition of claim 14 to the subject.

17. A method of treating and/or preventing an eye disease or disorder in a subject in need thereof, the method comprising administering the composition of claim 14 to the subject.

18. A method of treating and/or preventing a kidney disease or disorder in a subject in need thereof, the method comprising administering the pharmaceutical composition of claim 14 to the subject.

19. A method of treating and/or preventing an ear disease or disorder in a subject in need thereof, the method comprising administering the pharmaceutical composition of claim 14 to the subject.