SOCS mimetics for the treatment of diseases

Patent metadata

Field	Value
Publication number	US-11603387-B2
Application number	US-201515113725-A
Country	US
Kind code	B2
Filing date	Jan 23, 2015
Priority date	Jan 24, 2014
Publication date	Mar 14, 2023
Grant date	Mar 14, 2023

Abstract

The subject invention concerns peptide mimetics of SOCS proteins and methods of use. In one embodiment, a peptide mimetic of the invention binds to a SOCS1 and a SOCS3 target protein. In a specific embodiment, a peptide mimetic of the invention comprises the amino acid sequence of SEQ ID NO:1 and/or SEQ ID NO:2 and/or SEQ ID NO:51, or a functional fragment or variant thereof. In a further embodiment, a peptide of the invention can comprise multiple copies of the mimetic sequence. In one embodiment, a peptide of the invention comprises two or more copies of SEQ ID NO:1 and/or SEQ ID NO:2 and/or SEQ ID NO:51. In a specific embodiment, a peptide mimetic of the invention comprises the amino acid sequence of SEQ ID NO:3 and/or SEQ ID NO:4 to and/or SEQ ID NO:52, or a functional fragment or variant thereof. The subject invention also pertains to methods of treating and/or preventing autoimmune conditions and/or disorders. In one embodiment, one or more peptide mimetics of the invention are used to treat an autoimmune condition or disorder in a person or animal. In a specific embodiment, a mimetic of the invention is used to treat SLE in a person or animal. The subject invention also concerns methods for diagnosing and/or monitoring progression of SLE in a person or animal.

First claim

We claim:

1. A peptide mimetic of a suppressor of cytokine signaling (SOCS) protein that binds to and inhibits the activity of a tyrosine kinase, wherein said peptide mimetic comprises two copies of the SOCS1-kinase inhibitory region (KIR) amino acid sequence DTHFRTFRSHSDYRRI (SEQ ID NO: 1), and wherein said peptide mimetic comprises a linker amino acid sequence of five or more glycine amino acids positioned between and attached to a terminus of each of said two SOCS1-KIR amino acid sequences.

2. The peptide mimetic according to claim 1 , wherein said tyrosine kinase is a Janus kinase (JAK) protein.

3. The peptide mimetic according to claim 2 , wherein said JAK protein is JAK2.

4. The peptide mimetic according to claim 1 , wherein said peptide mimetic further comprises a nuclear localization sequence (NLS).

5. The peptide mimetic according to claim 1 , wherein said peptide mimetic further comprises a protein or nucleic acid that is attached to said peptide mimetic and that targets delivery to a cell and/or that provides for translocation of said peptide mimetic across a biological membrane of said cell.

6. The peptide mimetic according to claim 1 , wherein a lipophilic group is attached to said peptide mimetic.

7. The peptide mimetic according to claim 6 , wherein said lipophilic group is a palmitoyl-lysine group.

8. The peptide mimetic according to claim 6 , wherein said lipophilic group comprises one or more arginine and/or lysine amino acids at the N-terminus, the C-terminus, or both the N-terminus and C-terminus of said peptide mimetic.

9. The peptide mimetic according to claim 8 , wherein said peptide mimetic comprises the amino acid sequence of SEQ ID NO: 29.

10. The peptide mimetic according to claim 6 , wherein said lipophilic group comprises a fatty acid moiety.

11. The peptide mimetic according to claim 10 , wherein said fatty acid is capric acid, lauric acid, myristic acid, palmitic acid, stearic acid, arachidic acid, behenic acid, lignoceric acid, or cerotic acid.

12. The peptide mimetic according to claim 1 , wherein said peptide mimetic binds to the activation loop of JAK2 and/or TYK2.

13. The peptide mimetic according to claim 1 , wherein said peptide mimetic consists of the amino acid sequence of SEQ ID NO: 3 and one or more arginine and/or lysine amino acids at the N-terminus, the C-terminus, or both the N-terminus and the C-terminus of said peptide mimetic.

14. The peptide mimetic according to claim 1 , wherein said peptide mimetic consists of the amino acid sequence of SEQ ID NO: 3 and wherein a lipophilic group is attached to said peptide mimetic.

15. The peptide mimetic according to claim 14 , wherein said lipophilic group is a palmitoyl-lysine group.

16. The peptide mimetic according to claim 14 , wherein said lipophilic group is a fatty acid moiety.

17. The peptide mimetic according to claim 16 , wherein said fatty acid is capric acid, lauric acid, myristic acid, palmitic acid, stearic acid, arachidic acid, behenic acid, lignoceric acid, or cerotic acid.

18. The peptide mimetic according to claim 1 , wherein a polyethylene glycol moiety is attached to said peptide mimetic.

19. The peptide mimetic according to claim 1 , wherein a cell-penetrating peptide (CPP) is attached to said peptide mimetic.

20. The peptide mimetic according to claim 19 , wherein said CPP comprises the amino acid sequence of one or more of SEQ ID NO: 31, SEQ ID NO: 32, SEQ ID NO: 33, SEQ ID NO: 34, SEQ ID NO: 35, SEQ ID NO: 36, SEQ ID NO: 37, SEQ ID NO: 38, SEQ ID NO: 39, SEQ ID NO: 40, SEQ ID NO: 41, SEQ ID NO: 42, SEQ ID NO: 43, SEQ ID NO: 44, SEQ ID NO: 45, SEQ ID NO: 46, SEQ ID NO: 47, SEQ ID NO: 48, or SEQ ID NO: 49.

21. The peptide mimetic according to claim 1 , wherein said peptide mimetic consists of the amino acid sequence of SEQ ID NO: 3 and wherein a polyethylene glycol moiety is attached to said peptide mimetic.

22. The peptide mimetic according to claim 1 , wherein said peptide mimetic consists of the amino acid sequence of SEQ ID NO: 3 and wherein a CPP is attached to said peptide mimetic.

23. The peptide mimetic according to claim 22 , wherein said CPP is the amino acid sequence of one or more of SEQ ID NO: 31, SEQ ID NO: 32, SEQ ID NO: 33, SEQ ID NO: 34, SEQ ID NO: 35, SEQ ID NO: 36, SEQ ID NO: 37, SEQ ID NO: 38, SEQ ID NO: 39, SEQ ID NO: 40, SEQ ID NO: 41, SEQ ID NO: 42, SEQ ID NO: 43, SEQ ID NO: 44, SEQ ID NO: 45, SEQ ID NO: 46, SEQ ID NO: 47, SEQ ID NO: 48, or SEQ ID NO: 49.

24. The peptide mimetic according to claim 1 , wherein said peptide mimetic consists of the amino acid sequence of SEQ ID NO: 3.

25. A composition comprising a peptide mimetic of claim 1 , wherein said composition further comprises a suitable carrier, diluent, or buffer; or
wherein said peptide mimetic is encapsulated in a liposome; or
wherein said composition further comprises one or more anticancer or antitumor compound, and/or one or more compound for treating an autoimmune or inflammatory disorder.

26. The composition according to claim 25 , wherein the one or more anticancer or antitumor compound is taxol, vinblastine, cyclophosamide, ifosfamide, 5-fluorouracil, hydroxyurea, adriamycin, bleomycin, etoposide, camptothecin, angiostatin, tamoxifen, Imatinib, Trastuzumab, Bortezomib, Carfilzomib, or Salinosporamide A.

27. A polynucleotide comprising a nucleotide sequence that encodes one or more of the peptide mimetic of claim 1 .

28. The polynucleotide according to claim 27 , wherein said polynucleotide comprises regulatory elements that provide for expression of said nucleotide sequence in a cell.

29. The polynucleotide according to claim 28 , wherein said cell is a bacterial cell.

30. The polynucleotide according to claim 28 , wherein said cell is a yeast cell, a plant cell, an insect cell, or a mammalian cell.

31. The polynucleotide according to claim 28 , wherein said cell is a human cell.

32. The polynucleotide according to claim 27 , wherein said polynucleotide further comprises a nucleotide sequence encoding a CPP attached to said peptide mimetic.

33. The polynucleotide according to claim 32 , wherein said CPP comprises the amino acid sequence of one or more of SEQ ID NO: 31, SEQ ID NO: 32, SEQ ID NO: 33, SEQ ID NO: 34, SEQ ID NO: 35, SEQ ID NO: 36, SEQ ID NO: 37, SEQ ID NO: 38, SEQ ID NO: 39, SEQ ID NO: 40, SEQ ID NO: 41, SEQ ID NO: 42, SEQ ID NO: 43, SEQ ID NO: 44, SEQ ID NO: 45, SEQ ID NO: 46, SEQ ID NO: 47, SEQ ID NO: 48, or SEQ ID NO: 49.

34. The polynucleotide according to claim 27 , wherein said polynucleotide further comprises a nucleotide sequence encoding a nuclear localization sequence (NLS).

35. The polynucleotide according to claim 27 , wherein said polynucleotide further comprises a nucleotide sequence encoding one or more arginine and/or lysine amino acids at the N-terminus, the C-terminus, or both the N-terminus and the C-terminus of said peptide mimetic.

Assignees

• Univ Florida

Inventors

• Johnson Howard M
• Larkin Joseph
• Ahmed Chulbul M
• Jager Lindsey

Classifications

• A61K31/675

  having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate · CPC title

• C12Q1/6883

  for diseases caused by alterations of genetic material · CPC title

• A61K31/337

  having four-membered rings, e.g. taxol · CPC title

• A61K31/7048

  having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin {, digitoxin or digoxin} · CPC title

• A61P29/00

  Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] · CPC title