# US 10,369,189 B2 · Compositions and methods for uncoupling TrkB receptor from PLC gamma 1 for the treatment of epilepsy and anxiety-like disorder

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- Number: US 10,369,189 B2
- Document ID: US10369189B2
- Status: Granted
- Kind: B2
- Application number: 14/281,584
- Filed: 2014-05-19
- Published: 2015-01-15
- Granted: 2019-08-06
- Earliest claimed: 2010-02-22
- Assignees: Duke University
- Applicants: Duke University
- Inventors: James O. McNamara; Xiao-Ping He; Yangzhong Huang; Bin Gu
- Web page: https://patentgrep.com/patent/US10369189B2

## CPC

- A61K 38/16: Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof {(enzyme inhibitors A61K38/005)}
- A61K 31/7105: Natural ribonucleic acids, i.e. containing only riboses attached to adenine, guanine, cytosine or uracil and having 3'-5' phosphodiester links
- A61K 38/04: Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof ({enzyme inhibitors A61K38/005;} gastrins {A61K38/2207}, somatostatins A61K38/31, melanotropins A61K38/34 {; protease inhibitors A61K38/55})
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- C07K 16/2863: {against receptors for growth factors, growth regulators}
- C07K 2317/33: Crossreactivity, e.g. for species or epitope, or lack of said crossreactivity
- C07K 2317/34: Identification of a linear epitope shorter than 20 amino acid residues or of a conformational epitope defined by amino acid residues
- 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)
- 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)

## Abstract

The invention provides pharmaceutical compositions and methods of use thereof for preventing or ameliorating disorders of the nervous system. More specifically, the invention provides pharmaceutical compositions, including phosphopeptides that when administered disrupt the physical interaction of TrkB with its signaling effector, phospholipase Cγ1 (PLCγ1). The invention further provides method of treatment comprising administering phosphopeptides that uncouple TrkB from PLCγ1 in order to prevent and/or ameliorate nervous system disorders such as epilepsy, anxiety, and seizures.

## Claims

### Claim 1

A method of uncoupling a receptor tyrosine kinase (RTK) from a signaling effector for treating a disorder of the nervous system in a subject, the method comprising inhibiting the physical interaction of an RTK with its signaling effector by administering a therapeutically effective amount of an interfering molecule to the subject,
wherein the disorder of the nervous system is epilepsy or anxiety,
and wherein the interfering molecule is a phosphopeptide comprising SEQ ID NO: 5.

### Claim 2

A method of uncoupling tyrosine receptor kinase B (TrkB) from a TrkB signaling effector for treating a disorder of the nervous system in a subject, the method comprising administering a therapeutically effective amount of an interfering molecule,
wherein the interfering molecule inhibits the physical interaction of TrkB with a signaling effector,
wherein the disorder of the nervous system is epilepsy or anxiety,
and wherein the interfering molecule is a phosphopeptide comprising SEQ ID NO: 5.

### Claim 3 (depends on 2)

The method of claim 2, wherein the TrkB signaling effector is PLCγ1.

### Claim 4 (depends on 2)

The method of claim 2, wherein the phosphopeptide comprises the amino acid sequence YGRKKRRQRRRLQNLAKASPVYLDI (SEQ ID NO: 1), wherein the amino acid at position 22 is phosphorylated; the amino acid sequence LQNLAKASPVYLDI (SEQ ID NO: 5); or the sequence YGRKKRRQRRRLQNLAKASPVpYLDI (SEQ ID NO: 3), wherein Y816 is phosphorylated (designated by p).

### Claim 5

A method of uncoupling tyrosine receptor kinase B (TrkB) from a signaling effector for preventing onset or limiting the progression of a disorder of the nervous system in a subject, the method comprising administering to said subject a therapeutically effective amount of an interfering molecule,
wherein the interfering molecule inhibits the physical interaction of TrkB with a signaling effector,
wherein the disorder of the nervous system is epilepsy or anxiety,
and wherein the interfering molecule is a phosphopeptide comprising SEQ ID NO: 5.

### Claim 6 (depends on 5)

The method of claim 5, wherein the TrkB signaling effector is PLCγ1.

### Claim 7 (depends on 5)

The method of claim 5, wherein the phosphopeptide comprises the amino acid sequence YGRKKRRQRRRLQNLAKASPVYLDI (SEQ ID NO: 1), wherein the amino acid at position 22 is phosphorylated; the amino acid sequence LQNLAKASPVYLDI (SEQ ID NO: 5); or the sequence YGRKKRRQRRRLQNLAKASPVpYLDI (SEQ ID NO: 3), wherein Y816 is phosphorylated (designated by p).

### Claim 8 (depends on 1, 2, 5)

The method according to claim 1, claim 2 or claim 5, wherein said subject is a mammal.

### Claim 9 (depends on 8)

The method according to claim 8, wherein said subject is a human.

### Claim 10

A method of preventing epileptic seizures in a subject in need thereof, the method comprising uncoupling tyrosine receptor kinase B (TrkB) from phospholipase C gamma 1 (PLCγ1) by administering a therapeutically effective amount of an interfering molecule, wherein the interfering molecule is a phosphopeptide comprising SEQ ID NO: 5.

### Claim 11

A method of ameliorating anxiety-like disorder in a subject in need thereof, the method comprising uncoupling tyrosine receptor kinase B (TrkB) from phospholipase C gamma 1 (PLCγ1) by administering a therapeutically effective amount of an interfering molecule, wherein the interfering molecule is a phosphopeptide comprising SEQ ID NO: 5.

### Claim 12 (depends on 10, 11)

The method of claim 10 or 11, wherein the phosphopeptide comprises the amino acid sequence YGRKKRRQRRRLQNLAKASPVYLDI (SEQ ID NO: 1), wherein the amino acid at position 22 is phosphorylated; the amino acid sequence LQNLAKASPVYLDI (SEQ ID NO: 5); or the sequence YGRKKRRQRRRLQNLAKASPVpYLDI (SEQ ID NO: 3), wherein Y816 is phosphorylated (designated by p).