Triblock peptide amphiphiles, micelles and methods of use

Patent metadata

Field	Value
Publication number	US-12006350-B2
Application number	US-201816760329-A
Country	US
Kind code	B2
Filing date	Oct 30, 2018
Priority date	Oct 30, 2017
Publication date	Jun 11, 2024
Grant date	Jun 11, 2024

Abstract

One aspect of the present invention is directed to triblock peptides comprising a lipid moiety, a peptide block and a zwitterion-like block. Another aspect of the invention is directed to pharmaceutical compositions comprising the triblock peptides of the present in invention arranged in micelles in a pharmaceutically acceptable carrier. In certain embodiments, the pharmaceutical compositions of the present invention are vaccine compositions, which may further comprise an adjuvant. Another aspect of the invention is directed to methods of using the triblock peptides and compositions of the invention to treat a disease or condition.

First claim

We claim:

1. A triblock peptide of the formula:
A-B-C
wherein
A is a lipid moiety, wherein the lipid moiety is PalmK or Palm2K; and
B and C are independently a peptide block or a zwitterion-like block, wherein one of B and C is a peptide block and the other of B and C is a zwitterion-like block;
wherein the peptide block is selected from the group consisting of SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 3, or SEQ ID NO: 4;
wherein the zwitterion-like block is (EK) 4 or (KE) 4 ; and
wherein the triblock peptide assembles into a micelle when in a liquid.

2. The triblock peptide of claim 1 , wherein the peptide block has a molecular weight from 75 g/mol to 80,000 g/mol.

3. The triblock peptide of claim 1 , wherein the zwitterion-like block has a molecular weight from 200 g/mol to 60,000 g/mol.

4. A triblock peptide of formula A-B-C, wherein one of A, B, and C is a lipid moiety, one of A, B, and C is a peptide block, and one of A, B, and C is a zwitterion-like block; wherein A, B, and C are in an arrangement selected from the group consisting of lipid-peptide-zwitterion, lipid-zwitterion-peptide, peptide-lipid-zwitterion, peptide-zwitterion-lipid, zwitterion-lipid-peptide, and zwitterion-peptide-lipid;
wherein the lipid moiety is PalmK or Palm2K;
wherein the peptide block is selected from the group consisting of SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 3, or SEQ ID NO: 4;
wherein the zwitterion-like block is (EK) 4 or (KE) 4 ; and
wherein the triblock peptide assembles into a micelle when in a liquid.

5. The triblock peptide of claim 1 , wherein the micelles are from 4 nm to 100 μm in greatest dimension.

6. The triblock peptide of claim 1 , wherein the micelles form structures selected from the group consisting of spheres, cylinders, worm-like structures and combinations thereof.

7. The triblock peptide of claim 1 , wherein the micelles form higher-order structures.

8. The triblock peptide of claim 7 , wherein the higher-order structures are selected from the group consisting of clusters, twines, braids, nets and combinations thereof.

9. The triblock peptide of claim 7 , wherein the higher-order structures are from 10 nm to 100 μm in greatest dimension.

10. The triblock peptide of claim 1 , wherein the peptides confined within the micelles form secondary structures.

11. The triblock peptide of claim 10 , wherein the secondary structures are selected from the group consisting of α-helix, β-sheet, triple helix, 3-10 helix, random coil and combinations thereof.

12. A pharmaceutical composition, the composition comprising a triblock peptide of the formula:
A-B-C
wherein
A is a lipid moiety, wherein the lipid moiety is PalmK or Palm2K; and
B and C are independently a peptide block or a zwitterion-like block, wherein one of B and C is a peptide block and the other of B and C is a zwitterion-like block;
wherein the peptide block is selected from the group consisting of SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 3, or SEQ ID NO: 4; and the zwitterion-like block is (EK) 4 or (KE) 4 ; and
a pharmaceutically acceptable carrier, wherein the triblock peptide is arranged in a micelle.

13. The pharmaceutical composition of claim 12 , wherein the composition is a vaccine composition and further comprises an immune effective amount of an adjuvant.

14. The pharmaceutical composition of claim 13 , wherein the adjuvant is selected from the group consisting of analgesic adjuvant, an inorganic compound, a mineral oil, a bacterial product, a delivery system, a cytokine, a food-based oil, a nonbacterial organic compound, an oligonucleotide, a plant based saponin and combinations thereof.

15. The pharmaceutical composition of claim 13 , wherein the adjuvant is selected from the group consisting of an aluminium salt, aluminium hydroxide, aluminium phosphate, a salt of calcium, iron or zinc, an insoluble suspension of acylated tyrosine or acylated sugars, cationically or anionically derivatised saccharides, polyphosphazenes, biodegradable microspheres, ceramide, monophosphoryl lipid A (MPLA), lipid A derivatives (e.g., of reduced toxicity), 3-O-deacylated MPL [3D-MPL], quit A, Saponin, QS21, Freund's Incomplete Adjuvant (Difco Laboratories, Detroit, Mich.), Merck Adjuvant 65 (Merck and Company, Inc., Rahway, N.J.), AS-2 (Smith-Kline Beecham, Philadelphia, Pa.), CpG oligonucleotides, poly(I:C), bioadhesives and mucoadhesives, microparticles, liposomes, polyoxyethylene ether formulations, polyoxyethylene ester formulations, muramyl peptides, squalamine and its derivatives, squalene and its derivatives, or imidazoquinolone compounds (e.g., imiquamod and its homologues), human immunomodulators, cytokines, interleukins (e.g., IL-1, IL-2, IL-4, IL-5, IL-6, IL-7, IL-12, etc.), macrophage colony stimulating factor (M-CSF), tumour necrosis factor (TNF), granulocyte, macrophage colony stimulating factor (GM-CSF) and combinations thereof.

16. The pharmaceutical composition of claim 12 , wherein the composition is selected from the group consisting of immunogenic compositions immunomodulatory compositions, and anti-cancer compositions.

17. The pharmaceutical composition of claim 12 , wherein the micelles are from 4 nm to 100 μm in greatest dimension.

18. The pharmaceutical composition of claim 12 , wherein the micelles form structures selected from the group consisting of spheres, cylinders, worm-like structures and combinations thereof.

19. The pharmaceutical composition of claim 12 , wherein the micelles form higher-order structures.

20. The pharmaceutical composition of claim 19 , wherein the higher-order structures are selected from the group consisting of clusters, twines, braids, nets and combinations thereof.

21. The pharmaceutical composition of claim 19 , wherein the higher-order structures are from 10 nm to 100 μm in greatest dimension.

22. The pharmaceutical composition of claim 12 , wherein the peptides confined within the micelles form secondary structures.

23. The pharmaceutical composition of claim 22 , wherein the secondary structures are selected from the group consisting of α-helix, β-sheet, triple helix, 3-10 helix, random coil and combinations thereof.

24. The triblock peptide of claim 1 , wherein the micelles form spheres.

25. The triblock peptide of claim 1 , wherein triblock peptide comprises double fatty acid lipid conjugation.

26. The triblock peptide of claim 1 , wherein the lipid moiety is PalmK.

27. The triblock peptide of claim 1 , wherein the lipid moiety is Palm2K.

28. The triblock peptide of claim 4 , wherein the lipid moiety is PalmK.

29. The triblock peptide of claim 4 , wherein the lipid moiety is Palm2K.

30. The pharmaceutical composition of claim 12 , wherein the lipid moiety is PalmK.

31. The pharmaceutical composition of claim 12 , wherein the lipid moiety is Palm2K.

32. The triblock peptide of claim 1 , wherein the peptide is selected from SEQ ID NO: 1 and SEQ ID NO: 2.

33. The triblock peptide of claim 4 , wherein the peptide is selected from SEQ ID NO: 1 and SEQ ID NO: 2.

34. The pharmaceutical composition of claim 12 , wherein the peptide is selected from SEQ ID NO: 1 and SEQ ID NO: 2.

Assignees

• Ulery Bret
• Zhang Rui
• Leeper Caitlin
• Smith Josiah
• Morton Logan
• Univ Missouri

Inventors

• Ulery Bret
• Zhang Rui
• Leeper Caitlin
• Smith Josiah
• Morton Logan

Classifications

• C07K14/57563

  Vasoactive intestinal peptide [VIP]; Related peptides · 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

• A61P31/16

  for influenza or rhinoviruses · CPC title

• A61P29/00

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

• C07K14/001

  by chemical synthesis · CPC title