Scorpion toxin analogue and method for treating autoimmune diseases

Patent metadata

Field	Value
Publication number	US-9708377-B2
Application number	US-201315032454-A
Country	US
Kind code	B2
Filing date	Oct 28, 2013
Priority date	Oct 28, 2013
Publication date	Jul 18, 2017
Grant date	Jul 18, 2017

Abstract

A novel peptide analogue of the Heterometrus spinnifer toxin HsTX1 is disclosed along with its application as, for example, a therapeutic agent for treating an autoimmune disease such as multiple sclerosis (MS) or rheumatoid arthritis (RA). The analogue comprises a peptide with an amino acid substitution at amino acid position 14 of the wild-type (WT) peptide sequence (or a position corresponding to position 14 of the WT peptide sequence). The analogue exhibits selectivity for Kv1.3 over Kv1.1 and other potassium channels relative to the WT peptide.

First claim

The invention claimed is:

1. A peptide analogue of Heterometrus spinnifer toxin HsTX1 comprising amino acid sequence SEQ ID NO:1, wherein the peptide analogue has an amino acid substitution corresponding to position 14 of SEQ ID NO:1 selected from the group consisting of an arginine (R) to phenylalanine (F) substitution, and an arginine (R) to 2-aminobutyric acid (Abu) substitution.

2. A method of inhibiting T lymphocyte proliferation in a subject, said method comprising administering to the subject an effective amount of a peptide analogue of Heterometrus spinnifer toxin HsTX1 comprising amino acid sequence SEQ ID NO:1, wherein the peptide analogue has an amino acid substitution corresponding to position 14 of SEQ ID NO:1, optionally in combination with a pharmaceutically acceptable carrier.

3. The method of claim 2 , wherein the amino acid substitution corresponding to position 14 of SEQ ID NO:1is selected from the group consisting of an arginine (R) to alanine (A) substitution (ie an R→A substitution), an arginine (R) to valine (V) substitution (ie an R→V substitution), an arginine (R) to phenylalanine (F) substitution (ie an R→F substitution), and an arginine (R) to 2-aminobutyric acid (Abu) substitution (ie an R→Abu substitution).

4. The method of claim 2 , wherein the amino acid substitution corresponding to position 14 of SEQ ID NO:1 is an arginine (R) to alanine (A) substitution (ie an R→A substitution).

5. The method of claim 2 , wherein the peptide analogue comprises an amino acid sequence selected from the group consisting of:

(SEQ ID NO: 2)

ASCRTPKDCADPCAKETGCPYGKCMNRKCKCNRC; 

(SEQ ID NO: 3)

ASCRTPKDCADPCVKETGCPYGKCMNRKCKCNRC; 

(SEQ ID NO: 4)

ASCRTPKDCADPCFKETGCPYGKCMNRKCKCNRC; 

and

(SEQ ID NO: 5) 

ASCRTPKDCADPCXKETGCPYGKCMNRKCKCNRC. 

where X is 2-aminobutyric acid (Abu).

6. The method of claim 2 , wherein the peptide analogue is a peptide that shows disulphide bridging between C3 and C24, C9 and C29, C13 and C31, and C19 and C34.

7. The method of claim 2 , wherein the peptide analogue consists of the amino acid sequence SEQ ID NO: 2.

8. The method of claim 2 , wherein the peptide analogue is in an isolated form.

9. The method of claim 2 , wherein the peptide analogue further comprises an amidated C-terminus.

10. A method of treating an autoimmune disease in a subject, said method comprising administering to the subject an effective amount of a peptide analogue of Heterometrus spinnifer toxin HsTX1 comprising amino acid sequence SEQ ID NO:1, wherein the peptide analogue has an amino acid substitution corresponding to position 14 of SEQ ID NO:1, optionally in combination with a pharmaceutically acceptable carrier.

11. The method of claim 10 , wherein the autoimmune disease to be treated is an autoimmune disease mediated by T EM cells.

12. The method of claim 10 , wherein the autoimmune disease to be treated is multiple sclerosis (MS) or rheumatoid arthritis (RA).

13. The method of claim 10 , wherein the amino acid substitution corresponding to position 14 of SEQ ID NO:1 is selected from the group consisting of an arginine (R) to alanine (A) substitution (ie an R→A substitution), an arginine (R) to valine (V) substitution (ie an R→V substitution), an arginine (R) to phenylalanine (F) substitution (ie an R→F substitution), and an arginine (R) to 2-aminobutyric acid (Abu) substitution (ie an R→Abu substitution).

14. The method of claim 10 , wherein the amino acid substitution corresponding to position 14 of SEQ ID NO:1 is an arginine (R) to alanine (A) substitution (ie an R→A substitution).

15. The method of claim 10 , wherein the peptide analogue comprises an amino acid sequence selected from the group consisting of:

(SEQ ID NO: 2)

ASCRTPKDCADPCAKETGCPYGKCMNRKCKCNRC;

(SEQ ID NO: 3)

ASCRTPKDCADPCVKETGCPYGKCMNRKCKCNRC;

and

(SEQ ID NO: 4)

ASCRTPKDCADPCFKETGCPYGKCMNRKCKCNRC;

(SEQ ID NO: 5)

ASCRTPKDCADPCXKETGCPYGKCMNRKCKCNRC,

where X is 2-aminobutyric acid (Abu).

16. The method of claim 10 , wherein the peptide analogue is a peptide that shows disulphide bridging between C3 and C24, C9 and C29, C13 and C31, and C19 and C34.

17. The method of claim 10 , wherein the peptide analogue consists of the amino acid sequence SEQ ID NO: 2.

18. The method of claim 10 , wherein the peptide analogue is in an isolated form.

19. The method of claim 10 , wherein the peptide analogue further comprises an amidated C-terminus.

Assignees

• Univ Monash
• Peptides Int Inc
• Baylor College Medicine

Inventors

• Norton Raymond S
• Kuyucak Serdar
• Rashid M Harunur
• Pennington Michael
• Beeton Christine

Classifications

• C07K14/43522 Primary

  from scorpions · CPC title

• A61P37/00

  Drugs for immunological or allergic disorders · 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

• A61K39/00

  Medicinal preparations containing antigens or antibodies (materials for immunoassay G01N33/53) · CPC title