Angiotensin (1-7) analogs and methods relating thereto

Patent metadata

Field	Value
Publication number	US-10829519-B2
Application number	US-201615759051-A
Country	US
Kind code	B2
Filing date	Sep 16, 2016
Priority date	Sep 18, 2015
Publication date	Nov 10, 2020
Grant date	Nov 10, 2020

Abstract

Angiotensin (1-7) analogs are provided. Also provided are methods of making such analogs methods for using analogs as therapeutic compositions such as, for example, treatment cancer.

First claim

What is claimed is:

1. A peptide, comprising:
(1) a compound of the formula R 1 —Z—R 9 —Y 1 , wherein:
R 1 is norleucine (Nle), leucine (L), alanine (A), norvaline (Nva), azidohomoalanine (Aha), or 2-Aminobutyric acid (Abu);
Z is an amino acid sequence having at least 85% identity to SEQ ID NO:1, wherein Z has the formula R 2 —R 3 —R 4 —R 5 —R 6 —R 7 —R 8 ;
R 9 is lysine (K), ornithine (Orn), 2,3-diaminopropionic acid (Dap), 2,4-diaminobutyric acid (Dab), or N-methyl lysine (NMe-K); and
Y 1 is absent or is a single amino acid extension or a two amino acid extension attached to R 9 ;
wherein R 1 —Z—R 9 has a cyclic structure, wherein R 1 or R 2 is connected to R 9 ; or (2) SEQ ID NO:5.

2. The peptide of claim 1 , wherein Z comprises one conservative amino acid substitution.

3. The peptide of claim 1 , wherein Z comprises one non-conservative amino acid substitution.

4. The peptide of claim 1 , wherein Z comprises one amino acid substitution in which the substitution is with alanine, phenylalanine, leucine, N-methyl tyrosine, N-methyl histidine, N-methyl isoleucine, or N-methyl valine.

5. The peptide of claim 1 , wherein the peptide comprises a lactam bridge between the amino acid at position R 2 and the amino acid at position R 9 .

6. The peptide of claim 1 , wherein R 1 is modified with a —COCH 3 or —NH 2 .

7. The peptide of claim 1 , wherein R 9 is modified by —NH 2 .

8. The peptide of claim 1 , wherein Y 1 is D-valine (dV)-D-proline (dP), (dV), (dP), or is absent.

9. The peptide of claim 1 , wherein R 2 is aspartic acid or alanine.

10. The peptide of claim 1 , wherein R 4 is valine, alanine, or N-methyl valine.

11. The peptide of claim 1 , wherein R 5 is tyrosine, N-methyl tyrosine, phenylalanine, or alanine.

12. The peptide of claim 1 , wherein R 6 is isoleucine, N-methyl isoleucine, alanine, or leucine.

13. The peptide of claim 1 , wherein R 7 is histidine, N-methyl histidine, or alanine.

14. The peptide of claim 1 , wherein R 8 is proline or alanine.

15. The peptide of claim 1 , wherein the peptide has an amino acid sequence selected from any one of SEQ ID NOs: 5, 6, or 8-31.

16. The peptide of claim 1 , wherein the peptide has an amino acid sequence of any one of SEQ ID NOs: 5, 6, 11, 15, 23, 27, or 31.

17. The peptide of claim 1 , wherein the peptide has the amino acid sequence set forth in SEQ ID NO:6.

18. The peptide of claim 1 , wherein the peptide has a half life at least 100 times longer than angiotensin (1-7) in biological conditions.

19. The peptide of claim 1 , wherein the peptide has an amino acid sequence of any one of SEQ ID NOs: 6, 11, 15, 23, 27, or 31.

20. A pharmaceutical composition comprising a pharmaceutically effective amount of the peptide of claim 1 and a pharmaceutically acceptable carrier.

21. The pharmaceutical composition of claim 20 , wherein the pharmaceutically effective amount comprises an amount that is sufficient to inhibit cell growth or proliferation, angiogenesis, or fibrosis.

22. The pharmaceutical composition of claim 20 , wherein the concentration of the peptide is in the range of 30 mg/ml to 100 mg/ml.

23. The pharmaceutical composition of claim 20 , wherein the amount of the peptide is in the range of 5 mg to 1 gram.

24. A method of reducing cancer cell growth or proliferation in a subject, the method comprising administering to a subject diagnosed with a cancer an effective amount of the peptide of claim 1 .

25. The method of claim 24 , wherein the cancer is prostate cancer, bladder cancer, bone cancer, brain cancer, breast cancer, colon cancer, cervical cancer, endometrial cancer, fallopian tube cancer, gastrointestinal cancer, genitourinary cancer, head and neck cancer, leukemia, lung cancer, lymphoma, melanoma, liver cancer, ovarian cancer, pancreatic cancer, peritoneal cancer, prostate cancer, renal cancer, skin cancer, or testicular cancer.

26. The method of claim 24 , further comprising administering a second therapeutic agent to the subject.

27. The method of claim 26 , wherein the second therapeutic agent is a chemotherapeutic agent.

28. The method of claim 24 , wherein a dosage of 100 mg/kg of body weight per day is administered to the subject.

29. A method of reducing angiogenesis in a cell, the method comprising administering to a subject diagnosed with a cancer an effective amount of the peptide of claim 1 .

30. A method of reducing fibrosis in a tissue, the method comprising administering to a subject an effective amount of the peptide of claim 1 .

Assignees

• Univ Wake Forest Health Sciences
• Tensive Controls Inc

Inventors

• Gallagher Patricia
• Tallant Ann
• Yohannes Daniel
• Gruber Kenneth A

Classifications

• C07K7/06 Primary

  having 5 to 11 amino acids · CPC title

• A61K38/00

  Medicinal preparations containing peptides (peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00) · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61K38/085

  Angiotensins · CPC title

• C07K7/14 Primary

  Angiotensins: Related peptides · CPC title