# US 12,006,350 B2 · Triblock peptide amphiphiles, micelles and methods of use

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- Number: US 12,006,350 B2
- Document ID: US12006350B2
- Status: Granted
- Kind: B2
- Application number: 16/760,329
- Filed: 2018-10-30
- Published: 2020-10-29
- Granted: 2024-06-11
- Earliest claimed: 2017-10-30
- Assignees: The Curators of the University of Missouri
- Applicants: Bret Ulery; Rui Zhang; Caitlin Leeper; Josiah Smith; Logan Morton
- Inventors: Bret Ulery; Rui Zhang; Caitlin Leeper; Josiah Smith; Logan Morton
- Web page: https://patentgrep.com/patent/US12006350B2

## CPC

- C07K 14/77: Ovalbumin
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 31/16: for influenza or rhinoviruses
- C07K 14/001: {by chemical synthesis}
- C07K 14/57563: {Vasoactive intestinal peptide [VIP]; Related peptides}
- 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)
- C07K: PEPTIDES (peptides in foodstuffs A23; obtaining protein compositions for foodstuffs, working-up proteins for foodstuffs A23J; preparations for medicinal purposes A61K; peptides containing beta-lactam rings C07D; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, C07D; ergot alkaloids of the cyclic peptide type C07D519/02; macromolecular compounds having statistically distributed amino acid units in their molecules, i.e. when the preparation does not provide for a specific; but for a random sequence of the amino acid units, homopolyamides and block copolyamides derived from amino acids C08G69/00; macromolecular products derived from proteins C08H1/00; preparation of glue or gelatine C09H; single cell proteins, enzymes C12N; genetic engineering processes for obtaining peptides C12N15/00; compositions for measuring or testing processes involving enzymes C12Q; investigation or analysis of biological material G01N33/00)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)

## 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.

## Claims

### 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.

### Claim 2 (depends on 1)

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

### Claim 3 (depends on 1)

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

### Claim 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.

### Claim 5 (depends on 1)

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

### Claim 6 (depends on 1)

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.

### Claim 7 (depends on 1)

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

### Claim 8 (depends on 7)

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.

### Claim 9 (depends on 7)

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

### Claim 10 (depends on 1)

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

### Claim 11 (depends on 10)

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.

### Claim 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.

### Claim 13 (depends on 12)

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

### Claim 14 (depends on 13)

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.

### Claim 15 (depends on 13)

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.

### Claim 16 (depends on 12)

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

### Claim 17 (depends on 12)

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

### Claim 18 (depends on 12)

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.

### Claim 19 (depends on 12)

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

### Claim 20 (depends on 19)

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.

### Claim 21 (depends on 19)

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

### Claim 22 (depends on 12)

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

### Claim 23 (depends on 22)

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.

### Claim 24 (depends on 1)

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

### Claim 25 (depends on 1)

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

### Claim 26 (depends on 1)

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

### Claim 27 (depends on 1)

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

### Claim 28 (depends on 4)

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

### Claim 29 (depends on 4)

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

### Claim 30 (depends on 12)

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

### Claim 31 (depends on 12)

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

### Claim 32 (depends on 1)

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

### Claim 33 (depends on 4)

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

### Claim 34 (depends on 12)

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