Scorpion toxin analogue and method for treating autoimmune diseases
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.
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.