# US 11,028,128 B2 · Inhibition of the aggregation of transthyretin by specific binding of peptides to aggregation-driving segments

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- Number: US 11,028,128 B2
- Document ID: US11028128B2
- Status: Granted
- Kind: B2
- Application number: 16/313,848
- Filed: 2017-06-29
- Published: 2020-01-09
- Granted: 2021-06-08
- Earliest claimed: 2016-06-30
- Assignees: The Regents of the University of California
- Applicants: The Regents of the University of California
- Inventors: David S. Eisenberg; Lorena Saelices Gomez
- Web page: https://patentgrep.com/patent/US11028128B2

## CPC

- C07K 7/08: having 12 to 20 amino acids (gastrins C07K14/595; somatostatins C07K14/655; melanotropins C07K14/68)
- C07K 7/06: having 5 to 11 amino acids
- C07K 14/00: Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- 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 2800/28: Neurological disorders
- G01N 2800/7047: Fibrils-Filaments-Plaque formation
- 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)
- 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)
- 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)

## Abstract

The invention disclosed herein relates to peptide inhibitors for transthyretin (TTR) aggregation and methods of inhibiting TTR aggregation, cytotoxicity, and/or TTR amyloidosis. Illustrative embodiments of the invention include a composition of matter comprising at least one peptide designed to inhibit the aggregation of TTR, with this peptide typically being coupled to a heterologous amino acid tag. A pharmaceutically acceptable carrier selected to be compatible with the inhibitory peptide may also be included. A method for blocking or inhibiting the aggregation of transthyretin TTR is also provided. The method comprises combining TTR with an effective amount of an inhibitory peptide or pharmaceutical composition, so that TTR aggregation and/or cytotoxicity is blocked or inhibited.

## Claims

### Claim 1

A pharmaceutical composition of matter comprising at least one peptide having the sequence:
(SEQ ID NO: 2)
PFHEHAEVVFTA;
(SEQ ID NO: 3)
PYSYSTTAVVTN;
(SEQ ID NO: 4)
HVAHPFVEFTE;
(SEQ ID NO: 5)
SYVTNPTSYAVT;
(SEQ ID NO: 6)
HFEVAFPVEHAT;
(SEQ ID NO: 7)
YVSNPTSTYVAT;
or
(SEQ ID NO: 8)
VANTSPTSYYVT;
wherein:
at least one of the amino acids in the at least one peptide comprises an amino acid comprising a N-methyl group moiety; and/or
the at least one peptide is coupled to a heterologous peptide tag comprising a plurality of arginine (R) amino acids; and
a pharmaceutically acceptable carrier, wherein the pharmaceutically acceptable carrier comprises an agent that inhibits microbial growth.

### Claim 2 (depends on 1)

The composition of claim 1, wherein the peptide is from 12 to 30 amino acids in length.

### Claim 3 (depends on 1)

The composition of claim 1, wherein the composition comprises a plurality of peptides.

### Claim 4

A method for reducing or inhibiting transthyretin (SEQ ID NO: 1) aggregation, comprising contacting transthyretin amyloid fibrils with at least one peptide comprising the sequence:
(SEQ ID NO: 2)
PFHEHAEVVFTA;
(SEQ ID NO: 3)
PYSYSTTAVVTN;
(SEQ ID NO: 4)
HVAHPFVEFTE;
(SEQ ID NO: 5)
SYVTNPTSYAVT;
(SEQ ID NO: 6)
HFEVAFPVEHAT;
(SEQ ID NO: 7)
YVSNPTSTYVAT;
or
(SEQ ID NO: 8)
VANTSPTSYYVT;
wherein:
at least one of the amino acids in the at least one peptide comprises an amino acid comprising a N-methyl group moiety; and/or
the at least one peptide is coupled to a heterologous peptide tag comprising a plurality of arginine (R) amino acids;
in an amount sufficient to reduce or inhibit transthyretin aggregation, so that transthyretin (SEQ ID NO: 1) aggregation is reduced or inhibited.

### Claim 5 (depends on 4)

The method of claim 4, wherein the transthyretin amyloid fibrils are within an in vivo environment.

### Claim 6

A method of observing the presence or absence of transthyretin amyloid fibrils in a biological sample comprising:
(a) combining a biological sample with a peptide having the sequence:
(SEQ ID NO: 2)
PFHEHAEVVFTA;
(SEQ ID NO: 3)
PYSYSTTAVVTN;
(SEQ ID NO: 4)
HVAHPFVEFTE;
(SEQ ID NO: 5)
SYVTNPTSYAVT;
(SEQ ID NO: 6)
HFEVAFPVEHAT;
(SEQ ID NO: 7)
YVSNPTSTYVAT;
or
(SEQ ID NO: 8)
VANTSPTSYYVT
(b) allowing the peptide to bind to transthyretin amyloid fibrils that may be present in the biological sample; and
monitoring combination (b) for the presence of complexes formed between transthyretin amyloid fibrils and the peptide; wherein the presence of said complexes show the presence of transthyretin amyloid fibrils in the biological sample.

### Claim 7 (depends on 6)

The method of claim 6, wherein the presence of complexes formed between transthyretin amyloid fibrils and the peptide is monitored using a detectable label that is coupled to the peptide.

### Claim 8 (depends on 7)

The method of claim 7, wherein the detectable label comprises a heterologous peptide tag.

### Claim 9 (depends on 6)

The method of claim 6, wherein the method is performed on a biological sample obtained from an individual suspected of suffering from wild-type or hereditary TTR amyloidosis.