# US 10,246,496 B2 · Potassium channel blockers and use thereof in the treatment of autoimmune diseases

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- Number: US 10,246,496 B2
- Document ID: US10246496B2
- Status: Granted
- Kind: B2
- Application number: 15/503,841
- Filed: 2015-08-14
- Published: 2017-12-21
- Granted: 2019-04-02
- Earliest claimed: 2014-08-15
- Assignees: La Trobe University; Monash University; Baylor College of Medicine; Peptides International, Inc.
- Applicants: Monash University; La Trobe University; Peptides International, Inc.; Baylor College of Medicine
- Inventors: Raymond S. Norton; Shih Chieh Chang; Michael W. Pennington; Christine Beeton; Brian J. Smith
- Web page: https://patentgrep.com/patent/US10246496B2

## CPC

- C07K 14/43595: {from coelenteratae, e.g. medusae}
- A61K 38/17: from animals; from humans {(enzyme inhibitors A61K38/005)}
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 35/00: Antineoplastic agents
- A61P 35/02: specific for leukemia
- A61P 37/00: Drugs for immunological or allergic disorders
- A61P 37/06: Immunosuppressants, e.g. drugs for graft rejection
- C07K 14/43504: {from invertebrates}
- C12N 15/63: Introduction of foreign genetic material using vectors; Vectors; Use of hosts therefor; Regulation of expression
- 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 4/00: Peptides having up to 20 amino acids in an undefined or only partially defined sequence; Derivatives thereof
- C07K 19/00: Hybrid peptides {, i.e. peptides covalently bound to nucleic acids, or non-covalently bound protein-protein complexes}
- C07K 2319/21: containing a His-tag
- 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)
- 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)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C12N: MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA (microbiological testing media C12Q1/00)

## Abstract

Novel analogues of the sea anemone Stichodactyla helianthus toxin ShK, and their use as, for example, therapeutic agents for treating autoimmune diseases are disclosed. The analogues comprise a ShK toxin polypeptide and an N-terminal extension comprising an amino acid sequence according to formula (I): wherein X−4 is D, E or other negatively-charged amino acid or derivative thereof, X−3 is E, I, L, S, V, W or a tryptophan derivative, X−2 is any amino acid, X−1 is any amino acid, a is absent or a first additional moiety, and b is absent or a second additional moiety. a-X−4X−3X−2X−1-b(SEQ ID NO: 3) (I)

## Claims

### Claim 1

An analogue of Stichodactyla helianthus toxin ShK comprising an ShK toxin polypeptide and an N-terminal extension selected from the group consisting ESSS (SEQ ID NO: 1), EWSS (SEQ ID NO: 2), EESS (SEQ ID NO: 5), EWST (SEQ ID NO: 6), EWTT (SEQ ID NO: 7), EWTS (SEQ ID NO: 8) and SEWSS (SEQ ID NO: 9).

### Claim 2 (depends on 1)

The analogue of claim 1, wherein the ShK toxin polypeptide comprises an amino acid sequence corresponding to:
RSCIDTIPKSRCTAFQCKHSMKYRLSFCRKTCGTC (SEQ ID NO: 4).

### Claim 3 (depends on 1)

The analogue of claim 1, wherein the ShK toxin polypeptide comprises a variant amino acid sequence including a substitution of Met21.

### Claim 4 (depends on 1)

The analogue of claim 1, wherein the N-terminal extension is EWSS (SEQ ID NO: 2).

### Claim 5 (depends on 1)

The analogue of claim 1, wherein the analogue is a polypeptide with disulphide bridging between Cys3-Cys35, Cys12-Cys28 and Cys17-Cys32.

### Claim 6 (depends on 1)

The analogue of claim 1, wherein the analogue is a polypeptide consisting of the amino acid sequence: EWSSRSCIDTIPKSRCTAFQCKHSMKYRLSFCRKTCGTC (SEQ ID NO: 10).

### Claim 7 (depends on 1)

The analogue of claim 1, further comprising a cell-penetrating peptide.

### Claim 8 (depends on 1)

The analogue of claim 1 in an isolated form.

### Claim 9 (depends on 1)

The analogue of claim 1, wherein the analogue is a polypeptide with an amidated C-terminal.

### Claim 10 (depends on 1)

A method of inhibiting T lymphocyte or class-switched B cell proliferation in a subject, said method comprising administering to the subject an effective amount of the analogue of claim 1, optionally in combination with a pharmaceutically acceptable carrier.

### Claim 11 (depends on 1)

A method of treating an autoimmune disease in a subject, said method comprising administering to the subject an effective amount of the analogue of claim 1, optionally in combination with a pharmaceutically acceptable carrier.

### Claim 12 (depends on 11)

The method of claim 11, wherein the autoimmune disease to be treated is an autoimmune disease mediated by TEM cells.

### Claim 13 (depends on 11)

The method of claim 11, wherein the autoimmune disease to be treated is rheumatoid arthritis (RA) or multiple sclerosis (MS).

### Claim 14 (depends on 1)

A method of treating a cancer in a subject, said method comprising administering to the subject an effective amount of the analogue of claim 1, optionally in combination with a pharmaceutically acceptable carrier.

### Claim 15 (depends on 14)

The method of claim 14, wherein the cancer is a solid tumour, leukaemia or lymphoma.