Stabilized polypeptide insulin receptor modulators

• US 10,227,390 B2
• Filed: 06/13/2014
• Issued: 03/12/2019
• Est. Priority Date: 06/14/2013
• Status: Expired due to Fees

• Current Assignee: President and Fellows of Harvard College (Harvard Corporation)
• Original Assignee: President and Fellows of Harvard College (Harvard Corporation)
• Inventors: Verdine, Gregory L., Hilinski, Gerard, Liang, Rebecca Yue, Nagel, Yvonne Alice, Zhou, Minyun
• Primary Examiner(s): Reynolds, Fred H
• Application Number:
  US14/898,222
• Publication Number:
  US 20160215036A1
• Time in Patent Office: 1,733 Days
• Field of Search: None
• CPC Class Codes: A61K 38/00 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 Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 17/02 for treating wounds, ulcers, burns, scars, keloids, or the like
• CPC Class Codes: A61P 25/02 for peripheral neuropathies
• CPC Class Codes: A61P 27/02 Ophthalmic agents
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: A61P 9/14 Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers
• CPC Class Codes: C07K 14/62 Insulins
• CPC Class Codes: C07K 14/72 for hormones for neuromediators C07K14/70571

Abstract

Provided herein are stabilized α-CT polypeptides comprising an alpha-helical segment, and wherein the polypeptide is of Formula (I-1) or Formula (I-2): R^f—[X_AA]_s—X_A1—X_A2—X_A3—X_A4—X_A5—X_A6—X_A7—X_A8—X_A9—X_A10—X_A11—X_A12—X_A13—X_A14—[X_AA]_t—R^e (I-1) R^f—[X_AA]_s—X_C1—X_C2—X_C3—X_C4—X_C5—X_C6—X_C7—X_C8—X_C9—X_C10—X_C11—X_C12—X_C13—X_C14—X_C15—X_C16—X_C17—X_C18—X_C19—X_C20—[X_AA]_t—R^e (I-2) wherein the α-CT polypeptide binds to the insulin receptor, and wherein the α-CT polypeptide includes at least one staple (i.e. two cross-linked amino acids) and/or at least one stitch (i.e. three cross-linked amino acids). Further provided are insulin analogs including the stapled or stitched α-CT polypeptides, pharmaceutical compositions thereof, methods of use, e.g., methods of treating a diabetic condition or complications thereof.

Claims

1. A polypeptide comprising an alpha-helical segment, wherein the polypeptide binds to the insulin receptor, and wherein the polypeptide is of Formula (I-2):

2. The polypeptide of claim 1, wherein each instance of the cross-linked amino acids is independently of Formula (i-d), (ii-d), (i-e), or (ii-e):

3. The polypeptide of claim 1, wherein R^3a is of Formula (G-1):

4. The polypeptide of claim 1, wherein L₁ is of Formula (G-4) or Formula (G-5):

5. The polypeptide of claim 1, wherein R^3b is of Formula (G-6):

6. The polypeptide of claim 1, wherein L₂ is of Formula (G-9) or Formula (G-10):

7. The polypeptide of claim 1, wherein is a single bond or a double bond.

8. An insulin analogue comprising:

(i) a polypeptide of claim 1;

(ii) an insulin A-chain polypeptide; and

(ii) an insulin B-chain polypeptide;

wherein

the polypeptide is linked to the insulin A chain polypeptide via a linker; and

the linker is optionally substituted alkylene-C(═

O)—

, optionally substituted heteroalkylene-C(═

O)—

, optionally substituted alkenylene-C(═

O)—

, optionally substituted heteroalkenylene-C(═

O)—

, optionally substituted alkynylene-C(═

O)—

, optionally substituted heteroalkynylene-C(═

O)—

, optionally substituted cycloalkylene-C(═

O)—

, optionally substituted heterocycloalkylene-C(═

O)—

, optionally substituted arylene-C(═

O)—

, optionally substituted heteroarylene-C(═

O)—

, optionally substituted aralkylene-C(═

O)—

, or optionally substituted heteroaralkylene-C(═

O)—

.

9. A pharmaceutical composition comprising a polypeptide of claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

10. A method of treating a diabetic condition or a complication thereof comprising administering to a subject in need thereof an effective amount of a polypeptide of claim 1 or a pharmaceutically acceptable salt thereof.

11. A method of treating a diabetic condition or a complication thereof comprising administering to a subject in need thereof an effective amount of an insulin analogue of claim 8 or a pharmaceutically acceptable salt thereof.

12. A method of lowering blood glucose levels in a subject comprising administering to the subject in need thereof an effective amount of a polypeptide of claim 1 or a pharmaceutically acceptable salt thereof.

13. A method of lowering blood glucose levels in a subject comprising administering to the subject in need thereof an effective amount of an insulin analogue of claim 8 or a pharmaceutically acceptable salt thereof.

14. A method of activating an insulin receptor comprising contacting the insulin receptor with an effective amount of a polypeptide of claim 1 or a pharmaceutically acceptable salt thereof.

15. The polypeptide of claim 1, wherein Rt is hydrogen;

unsubstituted aliphatic;

acetyl;

acyl;

or aliphatic substituted with ═

O; and

R^e is —

OR^E;

—

N(R^E)₂;

or —

SR^E, wherein each instance of R^E is, independently, hydrogen or unsubstituted aliphatic.

16. The polypeptide of claim 1, wherein n is 1.