Neuroprotective beta amyloid core peptides and peptidomimetic derivatives

Patent metadata

Field	Value
Publication number	US-11970521-B2
Application number	US-201716326777-A
Country	US
Kind code	B2
Filing date	Aug 15, 2017
Priority date	Aug 20, 2016
Publication date	Apr 30, 2024
Grant date	Apr 30, 2024

Abstract

Peptide analogues of β-amyloid and methods of using said analogues for neuroprotection are described herein. The β-amyloid peptide analogues have a sequence that is at least 50% identical to an N-terminal β-amyloid core fragment. A pharmaceutical composition of the β-amyloid peptide analogues in a pharmaceutically acceptable carrier can be administered to a subject for neuromodulation. The β-amyloid peptide analogues, while lacking neurotoxicity, effectively provides for protective activity against β-amyloid toxicity.

First claim

What is claimed is:

1. A modified, neuroprotective β-amyloid peptide analogue for use in treating Alzheimer's Disease, wherein the peptide analogue comprises a sequence at least 50% identical to YEVHHQ (SEQ ID NO. 1), with the caveat that Y is preserved and HH is preserved, wherein a backbone amide of at least one of the residues in the peptide analogue is N-methylated, wherein the peptide analogue ends at the Q of SEQ ID NO. 1.

2. The peptide analogue of claim 1 , wherein at least one of the residues in SEQ ID NO. 1 is a D-amino acid, a β-substituted amino acid, or a peptide isostere.

3. The peptide analogue of claim 1 , wherein the sequence is at least 60% identical to SEQ ID NO. 1.

4. The peptide analogue of claim 1 , wherein the sequence is at least 80% identical to SEQ ID NO. 1.

5. The peptide analogue of claim 1 , wherein the peptide analogue is non-toxic and provides protective activity against β-amyloid toxicity.

6. The peptide analogue of claim 1 , wherein the peptide analogue comprises an N-terminal modification, a C-terminal modification, or both.

7. The peptide analogue of claim 1 , wherein the peptide analogue is cyclized.

8. The peptide analogue of claim 1 , wherein the Q residue is conservatively substituted with H.

9. A modified, neuroprotective β-amyloid peptide analogue of DAEFRHDSGYEVHHQ (SEQ ID NO. 2) for use in treating Alzheimer's Disease, wherein the peptide analogue comprises a sequence according to the following:

(SEQ ID NO. 3)

X 1 X 2 X 3 X 4 X 5 X 6 X 7 X 8 X 9 YX 11 X 12 HHX 15

wherein Y and HH are preserved, wherein the X 1 -X 9 residues are optionally present in the peptide analogue, wherein the X 1 -X 9 , X 11 -X 12 , and XD 15 residues are each independently selected from natural and unnatural amino acids, wherein a backbone amide of at least one of the residues in the peptide analogue is N-methylated, wherein the peptide analogue ends at the X 15 residue.

10. The peptide analogue of claim 9 , wherein the peptide analogue is at least 60% identical to YEVHHQ of SEQ ID NO. 2.

11. The peptide analogue of claim 9 , wherein the peptide analogue is at least 80% identical to YEVHHQ of SEQ ID NO. 2.

12. The peptide analogue of claim 9 , wherein at least one of the residues in SEQ ID NO. 3 is a D-amino acid, a β-substituted amino acid, or a peptide isostere.

13. The peptide analogue of claim 9 , wherein the peptide analogue is non-toxic and provides protective activity against β-amyloid toxicity.

14. The peptide analogue of claim 9 , wherein the peptide analogue comprises an N-terminal modification, a C-terminal modification, cyclization, or a combination thereof.

15. The peptide analogue of claim 9 , wherein X 15 is H.

16. A modified, neuroprotective β-amyloid peptide analogue comprising a sequence at least 60% identical to YEVHHX (SEQ ID NO: 7), wherein X is H, with the caveat that HHH is preserved, wherein a backbone amide of at least one of the residues in the peptide analogue is N-methylated.

Assignees

• Univ Arizona
• Univ Hawaii

Inventors

• Nichols Robert A
• FOREST Kelly
• Hruby Victor J

Classifications

• C07K14/4711 Primary

  Alzheimer's disease; Amyloid plaque core protein · CPC title

• A61K9/0019

  Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner (non-active ingredients are additionally classified in A61K47/00) · CPC title

• A61K9/0053

  Mouth and digestive tract, i.e. intraoral and peroral administration · 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

• A61K38/1716

  Amyloid plaque core protein · CPC title