Apelin polypeptides
The invention provides modified apelin polypeptides having increased stability, circulating half-life, and/or potency relative to the native apelin-13 polypeptide. Compositions comprising the modified apelin polypeptides and methods of using the polypeptides for treating cardiac disorders, such as heart failure, are also disclosed.
1. An isolated polypeptide comprising the amino acid sequence SEQ ID NO: 16.
2. The isolated polypeptide of claim 1 , wherein the polypeptide is acetylated at its amino terminus.
3. The isolated polypeptide of claim 1 , wherein the polypeptide is conjugated to a C1 to C25 saturated or unsaturated fatty acyl group optionally through a conjugation linker.
4. The isolated polypeptide of claim 3 , wherein the fatty acyl group is Tridecanoyl, Butanoyl, Hexanoyl, Hexadecanoyl, Butanedioyl, Octanedioyl, or Decanedioyl.
5. The isolated polypeptide of claim 3 , wherein the fatty acyl group is Octanoyl, Decanoyl, Dodecanoyl, Tridecanoyl, Tetradecanoyl, Pentadecanoyl, Hexadecanoyl, Heptadecanoyl, Octadecanoyl, or Octadecandioyl.
6. The isolated polypeptide of claim 3 , wherein the conjugation linker comprises Aeea, Aeea-Aeea, γGlu-Aeea, γGlu-Aeea-Aeea, or γGlu.
7. The isolated polypeptide of claim 1 , wherein the polypeptide is conjugated to a polyethylene glycol (PEG) polymer optionally through a conjugation linker.
8. The isolated polypeptide of claim 7 , wherein the PEG polymer is a 5 kDa, 10 kDa, or 20 kDa PEG polymer.
9. The isolated polypeptide of claim 7 , wherein the conjugation linker comprises 3-mercaptopropanoic acid.
10. The isolated polypeptide of claim 1 , wherein the polypeptide is conjugated to an immunoglobulin or an immunoglobulin Fc domain optionally through a conjugation linker.
11. The isolated polypeptide of claim 10 , wherein the conjugation linker is a peptidyl linker.
12. The isolated polypeptide of claim 10 , wherein the conjugation linker is a non-peptidyl linker.
13. The isolated polypeptide of claim 12 , wherein the non-peptidyl linker comprises a PEG polymer.
14. The isolated polypeptide of claim 1 wherein the polypeptide has increased stability relative to wild-type apelin 13 (SEQ ID NO: 4) or pyroglutamated wild-type apelin-13 (SEQ ID NO: 6).
15. A pharmaceutical composition comprising the isolated polypeptide of claim 14 and a pharmaceutically acceptable carrier.
16. A method of improving cardiac contractility in a subject having a cardiovascular condition comprising administering to the subject the polypeptide of claim 1 wherein cardiac contractility is improved in the subject following administration.
17. A method of increasing ejection fraction in a subject having a cardiovascular condition comprising administering to the subject the polypeptide of claim 1 wherein the ejection fraction is increased following administration of the polypeptide.
18. A method for treating heart failure in a subject in need thereof comprising administering the polypeptide of claim 1 .
19. The method of claim 18 for improving cardiac contractility in a subject having a cardiovascular condition, wherein the cardiac contractility in the subject is improved following administration of the polypeptide.
20. The method of claim 18 wherein dP/dt max and/or ejection fraction, is increased in the subject following administration of the polypeptide.
21. The method of claim 18 wherein systolic or diastolic function is improved in the subject following administration of the polypeptide.
22. The method of claim 18 wherein the ejection fraction is increased in the subject following administration of the polypeptide.
23. The method of claim 18 , wherein the heart failure is heart failure with reduced ejection fraction.
24. The method of claim 18 , wherein the heart failure is heart failure with preserved ejection fraction.
25. The method of claim 18 , wherein the heart failure is chronic systolic heart failure or chronic diastolic heart failure.
26. The method of claim 18 , wherein the heart failure is acute heart failure.