# US 9,751,912 B2 · Neurotoxic target for amylospheroid, method and material for reducing the neurotoxicity of amylospheroid, and use thereof

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- Number: US 9,751,912 B2
- Document ID: US9751912B2
- Status: Granted
- Kind: B2
- Application number: 13/729,152
- Filed: 2012-12-28
- Published: 2013-07-04
- Granted: 2017-09-05
- Earliest claimed: 2011-12-29
- Assignees: Tao Health Life Pharma Co., Ltd.
- Applicants: TAO Health Life Pharma Co., Ltd.
- Inventors: Minako Hoshi
- Web page: https://patentgrep.com/patent/US9751912B2

## CPC

- C07K 5/1024: {with the first amino acid being heterocyclic}
- A61K 31/554: having at least one nitrogen and one sulfur as ring hetero atoms, e.g. clothiapine, diltiazem
- A61K 38/13: Cyclosporins
- A61K 38/1767: {from invertebrates}
- A61K 51/08: Peptides, e.g. proteins {, carriers being peptides, polyamino acids, proteins}
- A61P 25/28: for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07K 5/1016: {and aromatic or cycloaliphatic}
- C07K 5/1019: {with the first amino acid being basic}
- C07K 7/06: having 5 to 11 amino acids
- C07K 7/08: having 12 to 20 amino acids (gastrins C07K14/595; somatostatins C07K14/655; melanotropins C07K14/68)
- G01N 33/6896: {Neurological disorders, e.g. Alzheimer's disease}
- 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)
- G01N 2500/02: Screening involving studying the effect of compounds C on the interaction between interacting molecules A and B (e.g. A = enzyme and B = substrate for A, or A = receptor and B = ligand for the receptor)
- G01N 2800/2821: Alzheimer
- 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
- G01N: INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES (measuring or testing apparatus or processes other than immunoassay, involving enzymes or microorganisms C12M, C12Q)

## Abstract

In one or a plurality of embodiments, there is provided a target molecule of amylospheroid, which is expressed in mature neurons and to which the amylospheroid binds to induce death of cells. Further, in one or a plurality of embodiments, there is provided a method and a substance for inhibiting death of mature neurons induced by the amylospheroid. In one aspect, the present disclosure relates to a use of Na+/K+-ATPase α3 as a binding target molecule of amylospheroid. In another aspect, the present disclosure relates to a method for suppressing death of mature neurons induced by the amylospheroid, including inhibiting protein-protein interaction between the amylospheroid and the Na+/K+-ATPase α3, and the like.

## Claims

### Claim 1

A method for inhibiting protein-protein interaction between amylospheroid and Na+/K+-ATPase α3, consisting of causing at least one substance selected from a group consisting of a polypeptide, a peptide mimetic thereof, and anti-NAKα3 antibody to interact with ASPD or NAKα3, wherein length of the polypeptide is 50 or less amino acids, and wherein the polypeptide comprises the amino acid sequence of X1X2NW (SEQ ID NO:8) or X2NW (SEQ ID NO:49) at the N-terminal, wherein X1 is arginine, histidine, or lysine, and X2 is hydrophobic amino acid residue or glycine.

### Claim 2 (depends on 1)

A method according to claim 1, wherein the substance mimics a tertiary structure of a site of ASPD or NAKα3 participating in the protein-protein interaction between ASPD and NAKα3.

### Claim 3

A method for suppressing death of a mature neuron induced by amylospheroid, comprising inhibiting protein-protein interaction between the amylospheroid and Na+/K+-ATPase α3 by administering to a subject in need thereof at least one substance selected from a group consisting of a polypeptide, a peptide mimetic thereof, and anti-NAKα3 antibody, wherein length of the polypeptide is 50 or less amino acids, and wherein the polypeptide comprises the amino acid sequence of X1X2NW (SEQ ID NO:8) or X2NW (SEQ ID NO:49) at the N-terminal, wherein X1 is arginine, histidine, or lysine, and X2 is hydrophobic amino acid residue or glycine.

### Claim 4 (depends on 3)

A method according to claim 3, wherein the protein-protein interaction between the amylospheroid and the Na+/K+-ATPase α3 is inhibited by contact between the amylospheroid and the substance capable of performing competitive inhibition based on a surface tertiary structure of both or one of the amylospheroid and the Na+/K+-ATPase α3.

### Claim 5 (depends on 3)

A method according to claim 3, wherein the protein-protein interaction between the amylospheroid and the Na+/K+-ATPase α3 is inhibited by contact between the amylospheroid and the substance capable of binding to the amylospheroid by competition with the Na+/K+-ATPase α3.

### Claim 6

A method for preventing, ameliorating, and/or treating Alzheimer's disease and/or dementia with Lewy bodies, comprising suppressing death of a mature neuron induced by amylospheroid by inhibiting protein-protein interaction between the amylospheroid and Na+/K+-ATPase α3 by administering to a subject in need thereof at least one substance selected from a group consisting of a polypeptide, a peptide mimetic thereof, and anti-NAKα3 antibody, wherein length of the polypeptide is 50 or less amino acids, and wherein the polypeptide comprises the amino acid sequence of X1X2NW (SEQ ID NO: 8) or X2NW (SEQ ID NO: 49) at the N-terminal, wherein X1 is arginine, histidine, or lysine, and X2 is hydrophobic amino acid residue or glycine.

### Claim 7 (depends on 6)

A method according to claim 6, wherein the protein-protein interaction between the amylospheroid and the Na+/K+-ATPase α3 is inhibited by contact between the amylospheroid and the substance capable of performing competitive inhibition based on a surface tertiary structure of both or one of the amylospheroid and the Na+/K+-ATPase α3.

### Claim 8 (depends on 6)

A method according to claim 6, wherein the protein-protein interaction between the amylospheroid and the Na+/K+-ATPase α3 is inhibited by contact between the amylospheroid and the substance capable of binding to the amylospheroid by competition with the Na+/K+-ATPase α3.