Potassium channel blockers and use thereof in the treatment of autoimmune diseases

Patent metadata

Field	Value
Publication number	US-10246496-B2
Application number	US-201515503841-A
Country	US
Kind code	B2
Filing date	Aug 14, 2015
Priority date	Aug 15, 2014
Publication date	Apr 2, 2019
Grant date	Apr 2, 2019

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 −4 X −3 X −2 X −1 -b(SEQ ID NO: 3)  (I)

First claim

The invention claimed is:

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).

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

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

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

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

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

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

8. The analogue of claim 1 in an isolated form.

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

10. 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.

11. 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.

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

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

14. 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.

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

Assignees

• Univ Monash
• Univ La Trobe
• Peptides Int Inc
• Baylor College Medicine

Inventors

• Norton Raymond S
• Chang Shih Chieh
• Pennington Michael W
• Beeton Christine
• Smith Brian J

Classifications

• A61P37/06

  Immunosuppressants, e.g. drugs for graft rejection · CPC title

• A61P37/00

  Drugs for immunological or allergic disorders · CPC title

• A61P35/02

  specific for leukemia · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61P29/00

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