Glucagon-receptor selective polypeptides and methods of use thereof

• US 10,501,517 B2
• Filed: 05/15/2017
• Issued: 12/10/2019
• Est. Priority Date: 05/16/2016
• Status: Active Grant

• Current Assignee: Intarcia Therapeutics, Inc.
• Original Assignee: Intarcia Therapeutics, Inc.
• Inventors: Blackwell, William, Srivastava, Ved P., Paulik, Mark A., Young, Andrew, Hunter, III, Robert Neil, Dock, Steven Thomas
• Primary Examiner(s): Garyu, Lianko G
• Application Number:
  US15/595,809
• Publication Number:
  US 20180009871A1
• Time in Patent Office: 939 Days
• Field of Search: None
• CPC Class Codes: A61K 38/26 Glucagons
• CPC Class Codes: A61K 9/0004 Osmotic delivery systems; Sustained release driven by osmosis, thermal energy or gas
• CPC Class Codes: A61M 2005/14513 with secondary fluid driving or regulating the infusion
• CPC Class Codes: A61M 31/002 Devices for releasing a drug at a continuous and controlled rate for a prolonged period of time artificial gland structures or devices A61F2/022; intra-uterine contraceptive devices A61F6/14; tampons for introducing into the vagina A61F13/20, A61L15/00; suppositories or bougies for intra-vaginal or intra-uterine application A61K9/02; physical forms of medicinal preparations for sustained or differential drug release A61K9/20, A61K9/50
• CPC Class Codes: A61M 5/14276 specially adapted for implantation
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/04 Centrally acting analgesics, e.g. opioids
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 3/00 Drugs for disorders of the metabolism of the blood or the extracellular fluid A61P7/00
• CPC Class Codes: A61P 3/04 Anorexiants; Antiobesity agents
• CPC Class Codes: A61P 3/08 for glucose homeostasis pancreatic hormones A61P5/48
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 31/00 Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 37/02 Immunomodulators
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 5/00 : Drugs for disorders of the endocrine system
• CPC Class Codes: A61P 7/00 : Drugs for disorders of the blood or the extracellular fluid
• CPC Class Codes: A61P 7/04 : Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
• CPC Class Codes: A61P 9/00 : Drugs for disorders of the cardiovascular system
• CPC Class Codes: C07K 14/00 : Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
• CPC Class Codes: C07K 14/605 : Glucagons

Abstract

This invention relates to isolated polypeptides that are glucagon-receptor selective analogs and peptide derivatives thereof. These analogs are selective for human glucagon receptor with improved solubility, thermal stability, and physicochemical properties as compared to native endogenous glucagon. This invention also relates to methods of using such polypeptides in a variety of therapeutic and diagnostic indications, as well as methods of producing such polypeptides. These analogs are useful, alone or in combination with other therapeutic peptides, in methods of treating obesity, diabetes, metabolic disorders, and other disorders or disease.

Claims

1. An isolated polypeptide comprising:

(i) the amino acid sequence;

X₁X₂X₃GTFTSDX₁₀X₁₁X₁₂X₁₃LX₁₅X₁₆X₁₇X₁₈AQEFX₂₃X₂₄X₂₅LEDE-Z-tail (SEQ ID NO;

     1), wherein;

X₁ is Y or W;

X₂ is S, G or T;

X₃ is Q or H;

X₁₀ is Y or H;

X₁₁ is S or T;

X₁₂ is K or R;

X₁₃ is Y, L or W;

X₁₅ is D or E;

X₁₆ is S, 2-Aminoisobutyric acid (Aib), A, E, L, Q, K, or I;

X₁₇ is K, E, S, T, or A;

X₁₈ is A, R, S, E, L, T or Y;

X₂₃ is T or V;

X₂₄ is K, I, L, or Aib;

X₂₅ is H or W; and

Z-tail is absent;

or is selected from the group consisting of EEPSSGAPPPS-OH (SEQ ID NO;

     4);

EPSSGAPPPS-OH (SEQ ID NO;

     5);

GAPPPS-OH (SEQ ID NO;

     6);

GGPSSGAPPPS-OH (SEQ ID NO;

     7);

GPSSGAPPPS-OH (SEQ ID NO;

     8);

KRNKNPPPS-OH (SEQ ID NO;

     9);

KRNKNPPS-OH (SEQ ID NO;

     10);

KRNKPPIA-OH (SEQ ID NO;

     11);

KRNKPPPA-OH (SEQ ID NO;

     150);

KRNKPPPS-OH (SEQ ID NO;

     12);

KSSGKPPPS-OH (SEQ ID NO;

     13);

PESGAPPPS-OH (SEQ ID NO;

     14);

PKSGAPPPS-OH (SEQ ID NO;

     15);

PKSKAPPPS-NH₂ (SEQ ID NO;

     16);

PKSKAPPPS-OH (SEQ ID NO;

     17);

PKSKEPPPS-NH₂ (SEQ ID NO;

     18);

PKSKEPPPS-OH (SEQ ID NO;

     19);

PKSKQPPPS-OH (SEQ ID NO;

     20);

PKSKSPPPS-NH₂ (SEQ ID NO;

     21);

PKSKSPPPS-OH (SEQ ID NO;

     22);

PRNKNNPPS-OH (SEQ ID NO;

     23);

PSKGAPPPS-OH (SEQ ID NO;

     24);

PSSGAPPPSE-OH (SEQ ID NO;

     25);

PSSGAPPPS-NH₂ (SEQ ID NO;

     26);

PSSGAPPPS-OH (SEQ ID NO;

     27);

PSSGAPPPSS-OH (SEQ ID NO;

     28);

PSSGEPPPS-OH (SEQ ID NO;

     29);

PSSGKKPPS-OH (SEQ ID NO;

     30);

PSSGKPPPS-NH₂ (SEQ ID NO;

     31);

PSSGKPPPS-OH (SEQ ID NO;

     32);

PSSGSPPPS-OH (SEQ ID NO;

     33);

PSSKAPPPS-OH (SEQ ID NO;

     34);

PSSKEPPPS-OH (SEQ ID NO;

     35);

PSSKGAPPPS-OH (SEQ ID NO;

     36);

PSSKQPPPS-OH (SEQ ID NO;

     37);

PSSKSPPPS-OH (SEQ ID NO;

     38);

SGAPPPS-OH (SEQ ID NO;

     39); and

SSGAPPPS-OH (SEQ ID NO;

     40);

or

(ii) the amino acid sequence;

YSQGTFTSDYSKYLDSX₁₇RAQX₂₁FVX₂₄WLX₂₇X₂₈T-OH (SEQ ID NO;

     137),

wherein;

X₁₇ is K*, where K* is in a lactam bridge with E* at X₂₁;

X₂₁ is E*, where E* is in a lactam bridge with K* at X₁₇;

X₂₄ is K or K**, where K** is in a lactam bridge with E** at X₂₈;

X₂₇ is Q or D; and

X₂₈ is E or E**, where E** is in a lactam bridge with K** at X₂₄;

or

(iii) the amino acid sequence;

X₁SX₃GTFTSDX₁₀SKYLDX₁₆X₁₇X₁₈AQX₂₁FVX₂₄WLEDEPX₃₁SX₃₃X₃₄PPPS-OH (SEQ ID NO;

     151),

wherein;

X₁=Y or W;

X₃=H or Q;

X₁₀=Y, K or K***;

X₁₆=A, S, Aib, K or K***;

X₁₇=A, K, Aib or K***;

X₁₈=Y, S or R;

X₂₁=E, K or K***;

X₂₄=I, Aib, K or K***;

X₃₁=S, K or K***;

X₃₃=G, K or K***; and

X₃₄=A or S;

wherein K*** is lysine, and the ε

-amino group of the lysine sidechain is covalently joined to a lipophilic substituent, optionally via a spacer.

2. The isolated polypeptide of claim 1, comprising the amino acid sequence:

X₁X₂X₃GTFTSDX₁₀X₁₁X₁₂X₁₃LX₁₅X₁₆X₁₇X₁₈AQEFX₂₃X₂₄X₂₅LEDE-Z-tail (SEQ ID NO;

     1), wherein;

X₁ is Y or W;

X₂ is S, G or T;

X₃ is Q or H;

X₁₀ is Y or H;

X₁₁ is S or T;

X₁₂ is K or R;

X₁₃ is Y, L or W;

X₁₅ is D or E;

X₁₆ is S, 2-Aminoisobutyric acid (Aib), A, E, L, Q, K, or I;

X₁₇ is K, E, S, T, or A;

X₁₈ is A, R, S, E, L, T or Y;

X₂₃ is T or V;

X₂₄ is K, I, L, or Aib;

X₂₅ is H or W; and

Z-tail is absent;

or is selected from the group consisting of EEPSSGAPPPS-OH (SEQ ID NO;

     4);

EPSSGAPPPS-OH (SEQ ID NO;

     5);

GAPPPS-OH (SEQ ID NO;

     6);

GGPSSGAPPPS-OH (SEQ ID NO;

     7);

GPSSGAPPPS-OH (SEQ ID NO;

     8);

KRNKNPPPS-OH (SEQ ID NO;

     9);

KRNKNPPS-OH (SEQ ID NO;

     10);

KRNKPPIA-OH (SEQ ID NO;

     11);

KRNKPPPA-OH (SEQ ID NO;

     150);

KRNKPPPS-OH (SEQ ID NO;

     12);

KSSGKPPPS-OH (SEQ ID NO;

     13);

PESGAPPPS-OH (SEQ ID NO;

     14);

PKSGAPPPS-OH (SEQ ID NO;

     15);

PKSKAPPPS-NH₂ (SEQ ID NO;

     16);

PKSKAPPPS-OH (SEQ ID NO;

     17);

PKSKEPPPS-NH₂ (SEQ ID NO;

     18);

PKSKEPPPS-OH (SEQ ID NO;

     19);

PKSKQPPPS-OH (SEQ ID NO;

     20);

PKSKSPPPS-NH₂ (SEQ ID NO;

     21);

PKSKSPPPS-OH (SEQ ID NO;

     22);

PRNKNNPPS-OH (SEQ ID NO;

     23);

PSKGAPPPS-OH (SEQ ID NO;

     24);

PSSGAPPPSE-OH (SEQ ID NO;

     25);

PSSGAPPPS-NH₂ (SEQ ID NO;

     26);

PSSGAPPPS-OH (SEQ ID NO;

     27);

PSSGAPPPSS-OH (SEQ ID NO;

     28);

PSSGEPPPS-OH (SEQ ID NO;

     29);

PSSGKKPPS-OH (SEQ ID NO;

     30);

PSSGKPPPS-NH₂ (SEQ ID NO;

     31);

PSSGKPPPS-OH (SEQ ID NO;

     32);

PSSGSPPPS-OH (SEQ ID NO;

     33);

PSSKAPPPS-OH (SEQ ID NO;

     34);

PSSKEPPPS-OH (SEQ ID NO;

     35);

PSSKGAPPPS-OH (SEQ ID NO;

     36);

PSSKQPPPS-OH (SEQ ID NO;

     37);

PSSKSPPPS-OH (SEQ ID NO;

     38);

SGAPPPS-OH (SEQ ID NO;

     39); and

SSGAPPPS-OH(SEQ ID NO;

     40).

3. The isolated polypeptide of claim 1, comprising an amino acid sequence selected from the group consisting of SEQ ID NOs:

41-48 50-136 and 143-149 (Compounds A1-A8 and A10-A103).

4. The isolated polypeptide of claim 1, comprising the amino acid sequence:

X₁X₂X₃GTFTSDX₁₀X₁₁X₁₂X₁₃LX₁₅X₁₆X₁₇X₁₈AQEFVX₂₄WLEDE-Z-tail (SEQ ID NO;

     2), wherein;

X₁ is Y or W;

X₂ is S or G;

X₃ is Q or H;

X₁₀ is Y or H;

X₁₁ is S or T;

X₁₂ is K or R;

X₁₃ is Y, L or W;

X₁₅ is D or E;

X₁₆ is 2-Aminoisobutyric acid (Aib), A, or S;

X₁₇ is A or K;

X₁₈ is R, S, L, or Y;

X₂₄ is K, I, or Aib; and

Z-tail is absent or is selected from the group consisting of PSSGAPPPS-NH₂ (SEQ ID NO;

     26);

PSSGAPPPS-OH (SEQ ID NO;

     27); and

PKSKSPPPS-NH₂ (SEQ ID NO;

     21).

5. The isolated polypeptide of claim 4, comprising an amino acid sequence selected from the group consisting of SEQ ID NOs:

41-43 and 143-149 (Compounds A1-A3 and A97-103).

6. The isolated polypeptide of claim 1, comprising the amino acid sequence:

YSX₃GTFTSDYSKYLDX₁₆X₁₇X₁₈AQEFVX₂₄WLEDE-Z-tail (SEQ ID NO;

     3), wherein;

X₃ is Q or H;

X₁₆ is 2-Aminoisobutyric acid (Aib) or A;

X₁₇ is A or K;

X₁₈ is R, S, or Y;

X₂₄ is K or Aib; and

Z-tail is selected from the group consisting of PSSGAPPPS-OH (SEQ ID NO;

     27) and PKSKSPPPS-NH₂ (SEQ ID NO;

     21).

7. The isolated polypeptide of claim 6, comprising an amino acid sequence selected from the group consisting of SEQ ID NOs:

41-43 (Compounds A1-A3).

8. The isolated polypeptide of claim 6, comprising an amino acid sequence of SEQ ID NO:

41 (Compound A1).

9. The isolated polypeptide of claim 6, comprising an amino acid sequence of SEQ ID NO:

42 (Compound A2).

10. The isolated polypeptide of claim 6, comprising an amino acid sequence of SEQ ID NO:

43 (Compound A3).

11. The isolated polypeptide of claim 6, consisting of an amino acid sequence of SEQ ID NO:

41 (Compound A1).

12. The isolated polypeptide of claim 6, consisting of an amino acid sequence of SEQ ID NO:

42 (Compound A2).

13. The isolated polypeptide of claim 6, consisting of an amino acid sequence of SEQ ID NO:

43 (Compound A3).

14. The isolated polypeptide of claim 1, comprising an amino acid sequence selected from the group consisting of SEQ ID NOs:

44-46 (Compounds A4-A6).

15. The isolated polypeptide of claim 1, comprising an amino acid sequence of SEQ ID NO:

44 (Compound A4).

16. The isolated polypeptide of claim 1, comprising an amino acid sequence of SEQ ID NO:

45 (Compound A5).

17. The isolated polypeptide of claim 1, comprising an amino acid sequence of SEQ ID NO:

46 (Compound A6).

18. The isolated polypeptide of claim 1, comprising an amino acid sequence selected from the group consisting of SEQ ID NOs:

47, 48, and 50-136 (Compounds A7, A8, and A10-A96).

19. The isolated polypeptide of claim 1, comprising the amino acid sequence:

YSQGTFTSDYSKYLDSX₁₇RAQX₂₁FVX₂₄WLX₂₇X₂₈T-OH (SEQ ID NO;

     137), wherein;

X₁₇ is K*, where K* is in a lactam bridge with E* at X₂₁;

X₂₁ is E*, where E* is in a lactam bridge with K* at X₁₇;

X₂₄ is K or K**, where K** is in a lactam bridge with E** at X₂₈;

X₂₇ is Q or D; and

X₂₈ is E or E**, where E** is in a lactam bridge with K** at X₂₄.

20. The isolated polypeptide of claim 19, comprising the amino acid sequence of SEQ ID NO:

138 (Compound A104) or SEQ ID NO;

139 (Compound A105).

21. The isolated polypeptide of claim 1, comprising the amino acid sequence:

X₁SX₃GTFTSDX₁₀SKYLDX₁₆X₁₇X₁₈AQX₂₁FVX₂₄WLEDEPX₃₁SX₃₃X₃₄PPPS-OH (SEQ ID NO;

     151),

wherein;

X₁=Y or W;

X₃=H or Q;

X₁₀=Y, K or K***;

X₁₆=A, S, Aib, K or K***;

X₁₇=A, K, Aib or K***;

X₁₈=Y, S or R;

X₂₁=E, K or K***;

X₂₄=I, Aib, K or K***;

X₃₁=S, K or K***;

X₃₃=G, K or K***; and

X₃₄=A or S;

wherein K*** is lysine, and the ε

-amino group of the lysine sidechain is covalently joined to a lipophilic substituent, optionally via a spacer.

22. The isolated polypeptide of claim 21, wherein each lipophilic substituent is covalently bound to the peptide via a spacer, and wherein each lipophilic substituent and spacer are of Formula II:

23. The isolated polypeptide of claim 21, wherein each lipophilic substituent is covalently bound to the peptide via a spacer, and wherein each lipophilic substituent and spacer are of Formula III:

24. The isolated polypeptide of claim 21, selected from the group consisting of SEQ ID NOs:

152-183 (Compounds B1-B32).

25. The isolated polypeptide of claim 24, selected from the group consisting of SEQ ID NOs:

154 (Compound B3), 157 (Compound B6), 158 (Compound B7), 160 (Compound B9), 161 (Compound B10), 162 (Compound B11), 165 (Compound B14), 166 (Compound B15), 168 (Compound B17), 172 (Compound B21), and 173 (Compound B22).

26. The isolated polypeptide of claim 21, wherein the isolated peptide is SEQ ID NO:

160 (Compound B9), 165 (Compound B14) or 166 (Compound B15).

27. A pharmaceutical composition comprising the isolated polypeptide of claim 1 or a pharmaceutically acceptable salt thereof.

28. The pharmaceutical composition of claim 27, further comprising a second polypeptide.

29. The pharmaceutical composition of claim 28, wherein the second polypeptide is an insulinotropic polypeptide.

30. The pharmaceutical composition of claim 28, wherein the second polypeptide is selected from the group consisting of exenatide, a derivative of exenatide, an analog of exenatide, glucagon-like peptide-1 (GLP-1), a derivative of GLP-1, and an analog of GLP-1.

31. The pharmaceutical composition of claim 28, wherein the second polypeptide is exenatide.

32. The pharmaceutical composition of claim 28, wherein the second polypeptide is a GLP-1 analog.

33. The pharmaceutical composition of claim 27, wherein the pharmaceutically acceptable salt is a trifluoroacetate salt, acetate salt or hydrochloride salt.

34. The pharmaceutical composition of claim 27, wherein the isolated polypeptide is selected from the group consisting of SEQ ID NOs:

41-43 (Compounds A1-A3).

35. The pharmaceutical composition of claim 27, wherein the isolated polypeptide comprises an amino acid sequence of SEQ ID NO:

41 (Compound A1), and wherein the pharmaceutically acceptable salt is a trifluoroacetate salt, acetate salt, or hydrochloride salt.

36. A particle formulation comprising the isolated polypeptide of claim 1 and at least one stabilizing component.

37. The particle formulation of claim 36, wherein the at least one stabilizing component is selected from the group consisting of one or more carbohydrates, one or more antioxidants, one or more amino acids, one or more buffers, one or more inorganic compounds, one or more surfactants, and combinations thereof.

38. A suspension formulation comprising the particle formulation of claim 36 and a suspension vehicle.

39. An osmotic delivery device, comprising the isolated polypeptide of claim 1.

40. The osmotic delivery device of claim 39, further comprising

an impermeable reservoir comprising interior and exterior surfaces and first and second open ends,

a semi-permeable membrane in sealing relationship with the first open end of the reservoir,

an osmotic engine within the reservoir and adjacent the semi-permeable membrane,

a piston adjacent the osmotic engine, wherein the piston forms a movable seal with the interior surface of the reservoir, the piston divides the reservoir into a first chamber and a second chamber, the first chamber comprising the osmotic engine,

a suspension formulation, wherein the second chamber comprises the suspension formulation and the suspension formulation is flowable and comprises the isolated polypeptide, and

a diffusion moderator inserted in the second open end of the reservoir, the diffusion moderator adjacent the suspension formulation.

41. The osmotic delivery device of claim 40, wherein the reservoir comprises titanium or a titanium alloy.

42. The osmotic delivery device of claim 40, wherein the suspension formulation comprises the particle formulation of claim 36 and a suspension vehicle.

43. A pharmaceutical composition comprising the isolated polypeptide of claim 1, wherein the isolated polypeptide is a glucagon analog and the composition further comprises an additional agent selected from the group consisting of exenatide, a derivative of exenatide, an analogue of exenatide, glucagon-like peptide-1 (GLP-1), a derivative of GLP-1, and an analogue of GLP-1.

44. The pharmaceutical composition of claim 43, wherein the additional agent is exenatide.

45. The pharmaceutical composition of claim 43, wherein the glucagon analog is selected from the group consisting of SEQ ID NOs:

41-48, 50-136, 138, 139, and 143-149 (Compounds A1-A8 and A10-A105).

46. The pharmaceutical composition of claim 45, wherein the glucagon analog is selected from the group consisting of SEQ ID NOs:

41, 42, 43, 44, 45, and 46 (Compounds A1, A2, A3, A4, A5 and A6).

47. The pharmaceutical composition of claim 43, wherein the glucagon analog is selected from the group consisting of SEQ ID NOs:

152-183 (Compounds B1-B32).

48. The pharmaceutical composition of claim 47, wherein the glucagon analog is selected from the group consisting of SEQ ID NOs:

154 (Compound B3), 157 (Compound B6), 158 (Compound B7), 160 (Compound B9), 161 (Compound B10), 162 (Compound B11), 165 (Compound B14), 166 (Compound B15), 168 (Compound B17), 172 (Compound B21), and 173 (Compound B22).

49. The pharmaceutical composition of claim 43, wherein the glucagon analog is formulated in combination with exenatide in a fixed ratio of glucagon analog:

exenatide of 1000;

1 to 1;

1000.

50. The pharmaceutical composition of claim 43, wherein the glucagon analog is formulated in combination with exenatide in a fixed ratio of glucagon analog:

exenatide of 100;

1 to 1;

100.

51. The pharmaceutical composition of claim 43, wherein the glucagon analog is formulated in combination with exenatide in a fixed ratio of glucagon analog:

exenatide of 10;

1 to 1;

10.

56. A method of treating or alleviating a symptom of a disease or disorder associated with aberrant glucagon activity in a subject in need thereof, the method comprising administering to the subject the isolated polypeptide of claim 1 or a pharmaceutical composition comprising the isolated polypeptide thereof.

57. The method of claim 56, wherein the disease or disorder is type 2 diabetes mellitus.

58. The method of claim 56, wherein the subject is a human.

59. The method of claim 56, wherein the isolated polypeptide or pharmaceutical composition is formulated for administration by a route selected from the group consisting of parenteral, oral, transdermal, transmucosal, rectal, intravenous, intradermal, subdermal, subcutaneous, and any combination thereof.

60. A method of:

(i) treating a metabolic disorder, obesity, metabolic disease or disorder associated with elevated blood glucose or

(ii) treating, delaying the onset of, delaying the progression of, or otherwise ameliorating a symptom of a disease or disorder in which co-agonism at both the glucagon and GLP-1 receptors is desired,

said method comprising administering the isolated polypeptide of claim 1 to a subject in need thereof.

61. The method of claim 60, wherein the metabolic disorder is type 2 diabetes mellitus.

52. An isolated polypeptide, wherein the isolated polypeptide is selected from the group consisting of SEQ ID NOs:

41-136, 138, 139, and 143-149 (Compounds A1-A105), and the isolated polypeptide is covalently joined to a lipophilic substituent, optionally via a spacer.

53. The isolated polypeptide of claim 52, wherein the isolated polypeptide is selected from the group consisting of SEQ ID NOs:

41-46 (Compounds A1-A6).

54. The isolated polypeptide of claim 52, wherein the lipophilic substituent is covalently bound to the peptide via a spacer, and the lipophilic substituent and spacer are of Formula II:

55. The isolated polypeptide of claim 52, wherein the lipophilic substituent is covalently bound to the peptide via a spacer, and the lipophilic substituent and spacer are of Formula III: