# US 10,774,114 B2 · Respiratory syncytial virus (RSV) replication inhibitors

> Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt

- Number: US 10,774,114 B2
- Document ID: US10774114B2
- Status: Granted
- Kind: B2
- Application number: 15/125,309
- Filed: 2015-03-10
- Published: 2017-06-01
- Granted: 2020-09-15
- Earliest claimed: 2014-03-10
- Assignees: Fondation the Ark
- Applicants: Fondation the Ark
- Inventors: Origéne Nyanguile; Jean-François Eleouet; Marie Galloux
- Web page: https://patentgrep.com/patent/US10774114B2

## CPC

- C07K 14/005: from viruses
- C07K 14/135: Respiratory syncytial virus
- 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)
- C07K 2319/10: containing a tag for extracellular membrane crossing, e.g. TAT or VP22
- C12N 2760/18522: New viral proteins or individual genes, new structural or functional aspects of known viral proteins or genes
- C12N 2760/18533: Use of viral protein as therapeutic agent other than vaccine, e.g. apoptosis inducing or anti-inflammatory
- 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)
- C12N: MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA (microbiological testing media C12Q1/00)

## Abstract

The invention provides polypeptides interacting with the binding of the RSV phosphoprotein P with the RSV nucleoprotein N and methods of using such polypeptides in the treatment and/or prevention of RSV infection.

## Claims

### Claim 1

A polypeptide that interacts or interferes with the binding of the RSV nucleoprotein N with the RSV phosphoprotein P by disrupting, impairing and/or displacing the N0-P interaction, wherein said polypeptide is internally cross-linked and is selected from:
an amino acid sequence: A11 A12 A13 A14 A15 A16 A17 A18 A19 A20 A21 A22 A23 A24 A25 A26 A27 A28 A29 A30 (SEQ ID NO: 2); or
an amino acid sequence: A7 A8 A9 A10 A11 A12 A13 A14 A15 A16 A17 A18 A19 A20 A21 A22 A23 A24 A25 A26 A27 A28 A29 A30 (SEQ ID NO: 3);
or a fragment thereof, wherein the fragment contains at least 15 contiguous amino acids of SEQ ID NO: 3;
or a pharmaceutically acceptable salt thereof;
and wherein said polypeptide includes at least two modified amino acids that together form an internal cross-link wherein said internally cross-linked amino acids are located at positions selected from A15, A16, A18, A19, A22, A23, A26, A27, A29, and A30 and are separated by 2 (i, i+3), 3 (i, i+4) or 6 (i, i+7) amino acids, and wherein those modified amino acids are selected from R,S-bis-pentenyl-glycine, S-pentenyl-alanine, R-pentenyl-alanine, S-octenyl-alanine and R-octenyl-alanine and wherein:
A7 is Glu, or any other polar negatively charged amino acid,
A8 is Phe or Trp, or any other large aromatic amino acid,
A9 is His,
A10 is Gly or Ala,
A11 is Glu or Asn,
A12 is Asp or Gin,
A13 is Ala, Gly, Val, Leu, Ile, Phe, Met or Trp,
A14 is Asn or Gln,
A15 is Asn or Gln,
A16 is Lys or Arg,
A17 is Ala, Gly, Val, Leu, Ile, Phe, Met or Trp or any other nonpolar amino acid,
A18 is Thr, Val, Ile or Leu,
A19 is Lys or Arg,
A20 is Phe or Trp, or any other large aromatic amino acid,
A21 is Leu, Gly, Val, Ile, Phe, Met or Trp or any other nonpolar amino acid,
A22 is Glu or Asp,
A23 is Ser, Ala, Thr or Gly,
A24 is Ile, Gly, Val, Leu, Phe, Met or Tip or any other nonpolar amino acid,
A25 is Lys or Arg,
A26 is Gly, Ala, Val, Leu or Ile,
A27 is Lys or Arg,
A28 is Phe, Tyr or Tip, or any other nonpolar amino acid,
A29 is Ala, Gly, Val, Leu, Ile, Phe, Met or Tip,
A30 is Ser.

### Claim 2 (depends on 1)

The polypeptide of claim 1, wherein said polypeptide comprises at least two modified amino acids at positions A16 and A23.

### Claim 3 (depends on 1)

The polypeptide of claim 1, wherein the internally cross-linked polypeptide consists of a biologically active sequence selected from the group consisting of SEQ ID No: 8 (HEVS 77), SEQ ID No: 15 (HEVS 112), SEQ ID No: 16 (HEVS 113), SEQ ID No: 17 (HEVS 114), SEQ ID No: 18 (HEVS 115), SEQ ID No: 19 (HEVS 116), SEQ ID No: 20 (HEVS 117), SEQ ID No: 22 (HEVS 120), SEQ ID No: 23 (HEVS 121), SEQ ID No: 26 (HEVS 124), SEQ ID No: 27 (HEVS 125), and SEQ ID No: 28 (HEVS 126).

### Claim 4 (depends on 1)

The polypeptide of claim 1 conjugated to an agent that increases the accumulation of said polypeptide in a cell.

### Claim 5 (depends on 4)

The polypeptide of claim 4, wherein the agent that increases the accumulation of said polypeptide in a cell is a cell membrane permeable carrier.

### Claim 6 (depends on 4)

The polypeptide of claim 4, wherein the cell membrane permeable carrier is a cell membrane peptide carrier.

### Claim 7 (depends on 5)

The polypeptide of claim 5, wherein the cell membrane peptide carrier is a positively charged amino acid peptide.

### Claim 8 (depends on 6)

The polypeptide of claim 6, wherein the positively charged amino acid peptide is selected from the group comprising the HIV-TAT 48-57 peptide [GRKKRRQRRR], the FHV-coat 35-49 peptide [RRRRNRTRRNRRRVR], the HTLV-II Rex 4-16 peptide [TRRQRTRRARRNR], the NYAD-1 peptide [ITFXDLLXYYGP, X=(S)-alpha-(2′-pentenyl) alanine], the BMV gag 7-25 peptide [KMTRAQRRAAARRNRWTAR] and the R9 peptide [RRRRRRRRR].

### Claim 9 (depends on 1)

The polypeptide of claim 1, said polypeptide comprising one or more amino acid in the L-form or in D-form, and/or in a retro-inverso isomer form.

### Claim 10 (depends on 1)

The polypeptide of claim 1, wherein the N-terminal end of the amino acid sequence of said polypeptide is covalently linked to one or more chemical entities selected from the group comprising an acetyl, a fatty acid, a cholesterol, a poly-ethylene glycol (PEG), a XTEN sequence, a nuclear localization signal, nuclear export signal, an antibody, a polysaccharide and a targeting molecule.

### Claim 11 (depends on 1)

The polypeptide of claim 1, said polypeptide comprising one or more non-conventional amino acids.

### Claim 12 (depends on 1)

A pharmaceutically acceptable salt of a polypeptide of claim 1.

### Claim 13 (depends on 1)

A pharmaceutical composition comprising at least one polypeptide of claim 1 and one or more pharmaceutically acceptable excipients, or vehicles, or carriers.

### Claim 14 (depends on 1)

A method of treating and/or preventing a RSV infection comprising administering an effective amount of at least one polypeptide of claim 1, a pharmaceutically acceptable salt of said polypeptide or a pharmaceutical composition of said polypeptide.

### Claim 15 (depends on 1)

An inhaler comprising an effective amount of at least one polypeptide of claim 1, a pharmaceutically acceptable salt of said polypeptide or a pharmaceutical composition of said polypeptide and a pharmaceutically acceptable propellant.

### Claim 16 (depends on 1)

A method of inhibiting the RSV replication by disrupting, impairing and/or displacing the N0-P interaction, the method comprising contacting at least one polypeptide of claim 1, a pharmaceutically acceptable salt of said polypeptide or a pharmaceutical composition of said polypeptide with a cell.

### Claim 17 (depends on 1)

The polypeptide of claim 1, wherein the internally cross-linked polypeptide consists of a biologically active sequence selected from the group consisting of SEQ ID NO: 8 (HEVS 77), SEQ ID NO: 22 (HEVS 120), SEQ ID NO: 26 (HEVS 124), SEQ ID NO: 27 (HEVS 125), and SEQ ID NO: 28 (HEVS 126), fragments containing at least 15 contiguous amino acids, or conservative variants thereof, wherein said variants are at least 80% identical to the respective sequences.