CPG15 and CPG15-2 compounds and inhibitors as insulin receptor and insulin-like growth factor receptor agonists and antagonists

• US 20070299010A1
• Filed: 02/09/2007
• Published: 12/27/2007
• Est. Priority Date: 02/10/2006
• Status: Active Grant

• Current Assignee: Massachusetts Institute of Technology
• Original Assignee: Massachusetts Institute of Technology
• Inventors: Nedivi, Elly
• Granted Patent: US 7,884,078 B2
• Time in Patent Office: Days
• US Class Current: 514/6.7
• CPC Class Codes: A61K 38/1709 from mammals
• CPC Class Codes: A61P 3/00 Drugs for disorders of the metabolism of the blood or the extracellular fluid A61P7/00
• CPC Class Codes: C12N 2501/105 Insulin-like growth factors [IGF]
• CPC Class Codes: C12N 2501/33 Insulin
• CPC Class Codes: C12N 5/0619 Neurons
• CPC Class Codes: C12N 5/0653 Adipocytes; Adipose tissue

Abstract

Disclosed herein are CPG15 and CPG15-2 compounds and inhibitors that act as agonists and antagonists of the insulin receptor and insulin-like growth factor receptors, and the use of such compositions for the treatment of insulin and insulin-like growth factor-related diseases.

Claims

1. A method of increasing the biological activity of an insulin-binding receptor in a mammalian cell, said method comprising contacting said cell with an insulin-binding receptor activator (IBRA) having at least one biological activity selected from the group consisting of:

a) the ability to promote cell survival;

b) the ability to promote neurite outgrowth; and

c) the ability to promote reduction of cell death;

wherein said inhibitor has the ability to bind to or activate an insulin-binding receptor.

2. The method of claim 1, wherein said insulin-binding receptor is an insulin receptor or IGF-1 receptor.

3. The method of claim 1, wherein said IBRA is a soluble-Candidate Plasticity Gene-15 (s-CPG15) or soluble Candidate Plasticity Gene-15-2 (s-CPG15-2) polypeptide.

4. The method of claim 3, wherein said s-CPG15 polypeptide comprises an amino acid sequence substantially identical to the sequence of SEQ ID NO:

1.

5. The method of claim 3, wherein said s-CPG15-2 polypeptide comprises an amino acid sequence substantially identical to the sequence of SEQ ID NO:

9.

6. The method of claim 1, wherein said biological activity of said insulin-binding receptor is at least one activity selected from the group consisting of:

a) binding of receptor substrate molecules;

b) phosphorylation of receptor substrate or downstream molecules;

c) glucose uptake;

d) insulin-induced immediate/early gene expression; and

e) ligand internalization.

7. The method of claim 1, wherein said insulin-binding receptor biological activity is increased by at least 20%.

8. The method of claim 1, wherein said cell is a neuron or an adipocyte.

9. A method of treating or preventing an insulin deficiency or insulin resistance disorder in a subject, said method comprising administering to said subject an IBRA having at least one biological activity selected from the group consisting of:

a) the ability to promote cell survival;

b) the ability to promote neurite outgrowth; and

c) the ability to promote reduction of cell death;

wherein said IBRA has the ability to bind to or activate an insulin-binding receptor, and wherein said IBRA is administered in an amount and for a time sufficient to treat or prevent said disorder in said subject.

10. The method of claim 9, wherein said insulin-binding receptor is an insulin receptor or IGF-1 receptor.

11. The method of claim 9, wherein said IBRA is an s-CPG15 or s-CPG15-2 polypeptide.

12. The method of claim 11, wherein said s-CPG15 polypeptide comprises an amino acid sequence substantially identical to the sequence of SEQ ID NO:

1.

13. The method of claim 11, wherein said s-CPG15-2 polypeptide comprises an amino acid sequence substantially identical to the sequence of SEQ ID NO:

9.

14. The method of claim 11, wherein said s-CPG15 or s-CPG15-2 polypeptide lacks a signal sequence.

15. The method of claim 14, wherein said s-CPG15 or s-CPG15-2 polypeptide lacks a signal sequence and a GPI linkage sequence.

16. The method of claim 11, wherein said s-CPG15 or s-CPG15-2 polypeptide comprises a post-translational modification.

17. The method of claim 16, wherein said post-translational modification comprises the attachment of a membrane component to said s-CPG15 or s-CPG15-2 polypeptide.

18. The method of claim 9, wherein said insulin deficiency or insulin resistance is reduced in said subject by at least 10%.

19. The method of claim 9, wherein said disorder is selected from the group consisting of Type I or Type II diabetes, hyperglycemia, hyperinsulinemia, dyslipidemia, obesity, polycystic ovarian disease, hypertension, cardiovascular disease, and syndrome X.

20. The method of claim 9, wherein said disorder is a neurological condition selected from the group consisting of Alzheimer'"'"'s disease, diabetic neuropathy, appetite control, neurodegeneration, and learning and memory impairment.

21. A method of treating or preventing IGF-1 deficiency or IGF-1 resistance disorder in a subject, said method comprising administering to said subject an IBRA having at least one biological activity selected from the group consisting of:

a) the ability to promote cell survival;

b) the ability to promote neurite outgrowth; and

c) the ability to promote reduction of cell death;

wherein said IBRA has the ability to bind to or activate an insulin-binding receptor, and wherein said IBRA is administered in an amount and for a time sufficient to treat or prevent said disorder in said subject.

22. The method of claim 21, wherein said insulin-binding receptor is an insulin receptor or IGF-1 receptor.

23. The method of claim 21, wherein said IBRA is an s-CPG15 or s-CPG15-2 polypeptide.

24. The method of claim 23, wherein said s-CPG15 polypeptide comprises an amino acid sequence substantially identical to the sequence of SEQ ID NO:

1.

25. The method of claim 23, wherein said s-CPG15-2 polypeptide comprises an amino acid sequence substantially identical to the sequence of SEQ ID NO:

9.

26. The method of claim 21, wherein said IGF-1 deficiency or IGF-1 resistance is reduced in said subject by at least 10%.

27. The method of claim 21, wherein said disorder is selected from the group consisting of amyotrophic lateral sclerosis, diabetic motor neuropathy, osteoporosis, immune modulation disorders, nephrotic syndrome, small stature, and decreased muscle mass.

28. A method of maintaining blood glucose levels within a normal range in a subject having elevated blood glucose levels, said method comprising administering to said subject an IBRA having at least one biological activity selected from the group consisting of:

a) the ability to promote cell survival;

b) the ability to promote neurite outgrowth; and

c) the ability to promote reduction of cell death;

wherein said IBRA has the ability to bind to or activate an insulin-binding receptor, and wherein said IBRA is administered in an amount and for a time sufficient to maintain the blood glucose levels of said subject within a normal range.

29. The method of claim 28, wherein said insulin-binding receptor is an insulin receptor or IGF-1 receptor.

30. The method of claim 28, wherein said IBRA is an s-CPG15 or s-CPG15-2 polypeptide.

31. The method of claim 30, wherein said s-CPG15 polypeptide comprises an amino acid sequence substantially identical to the sequence of SEQ ID NO:

1.

32. The method of claim 30, wherein said s-CPG15-2 polypeptide comprises an amino acid sequence substantially identical to the sequence of SEQ ID NO:

9.