# US 2011/0318352 A1 · Compositions and methods for the treatment of viral infections

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- Number: US 2011/0318352 A1
- Document ID: US20110318352A1
- Status: Published application
- Kind: A1
- Application number: 12/864,375
- Filed: 2010-07-23
- Published: 2011-12-29
- Earliest claimed: 2008-01-23
- Assignees: Dana-Farber Cancer Institute, Inc.
- Inventors: Loren D. Walensky
- Web page: https://patentgrep.com/patent/US20110318352A1

## CPC

- C07K 14/005: from viruses
- A61K 38/162: {from virus}
- A61K 39/145: Orthomyxoviridae, e.g. influenza virus
- A61K 39/155: Paramyxoviridae, e.g. parainfluenza virus
- A61K 39/21: Retroviridae, e.g. equine infectious anemia virus
- A61P 31/12: Antivirals
- A61P 31/14: for RNA viruses
- A61P 31/16: for influenza or rhinoviruses
- A61P 31/18: for HIV
- C07K 16/1145: {Env proteins, e.g. gp41, gp110/120, gp160, V3, principal neutralising domain [PND] or CD4-binding site}
- C07K 2317/76: Antagonist effect on antigen, e.g. neutralization or inhibition of binding
- C12N 2740/15022: New viral proteins or individual genes, new structural or functional aspects of known viral proteins or genes
- C12N 2740/15034: Use of virus or viral component as vaccine, e.g. live-attenuated or inactivated virus, VLP, viral protein
- C12N 2740/15071: Demonstrated in vivo effect
- C12N 2740/16122: New viral proteins or individual genes, new structural or functional aspects of known viral proteins or genes
- C12N 2740/16134: Use of virus or viral component as vaccine, e.g. live-attenuated or inactivated virus, VLP, viral protein
- C12N 2740/16171: Demonstrated in vivo effect
- C12N 2740/16222: New viral proteins or individual genes, new structural or functional aspects of known viral proteins or genes
- C12N 2740/16234: Use of virus or viral component as vaccine, e.g. live-attenuated or inactivated virus, VLP, viral protein
- C12N 2740/16271: Demonstrated in vivo effect
- C12N 2760/14022: New viral proteins or individual genes, new structural or functional aspects of known viral proteins or genes
- C12N 2760/14034: Use of virus or viral component as vaccine, e.g. live-attenuated or inactivated virus, VLP, viral protein
- C12N 2760/14071: Demonstrated in vivo effect
- C12N 2760/16022: New viral proteins or individual genes, new structural or functional aspects of known viral proteins or genes
- C12N 2760/16034: Use of virus or viral component as vaccine, e.g. live-attenuated or inactivated virus, VLP, viral protein
- C12N 2760/16071: Demonstrated in vivo effect
- C12N 2760/18022: New viral proteins or individual genes, new structural or functional aspects of known viral proteins or genes
- C12N 2760/18034: Use of virus or viral component as vaccine, e.g. live-attenuated or inactivated virus, VLP, viral protein
- C12N 2760/18071: Demonstrated in vivo effect
- C12N 2760/18522: New viral proteins or individual genes, new structural or functional aspects of known viral proteins or genes
- C12N 2760/18534: Use of virus or viral component as vaccine, e.g. live-attenuated or inactivated virus, VLP, viral protein
- C12N 2760/18571: Demonstrated in vivo effect
- C12N 2760/18622: New viral proteins or individual genes, new structural or functional aspects of known viral proteins or genes
- C12N 2760/18634: Use of virus or viral component as vaccine, e.g. live-attenuated or inactivated virus, VLP, viral protein
- C12N 2760/18671: Demonstrated in vivo effect
- 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
- 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 compositions, kits and methods utilizing polypeptides having a viral alpha-helix heptad repeat domain in a stabilized a-helical structure (herein also referred to as SAH). The compositions are useful for treating and/or preventing viral infections. The invention is based, at least in part, on the result provided herein demonstrating that viral hydrocarbon stapled alpha helical peptides display excellent proteolytic, acid, and thermal stability, restore the native alpha-helical structure of the peptide, are highly effective in interfering with the viral fusogenic process, and possess superior pharmacokinetic properties compared to the corresponding unmodified peptides.

## Claims

### Claim 1

A modified polypeptide comprising a stabilized alpha helix of HIV gp41 heptad repeat domain.

### Claim 2 (depends on 1)

The modified polypeptide of claim 1, wherein said stabilized HIV gp41 heptad repeat domain is stabilized with a hydrocarbon staple, two hydrocarbon staples, or more than two hydrocarbon staples.

### Claim 3

(canceled)

### Claim 4 (depends on 2)

The modified polypeptide of claim 2, wherein said modified polypeptide is 20 or more amino acids.

### Claim 5

(canceled)

### Claim 6 (depends on 2)

The modified polypeptide of claim 2, wherein said heptad repeat domain comprises the formula:
—W—W—I—Y—I—L—S-Q-N-E-L, or conservative amino acid substitutions thereof and wherein “-” can be any amino acid (SEQ ID NO: 44).

### Claim 7 (depends on 2)

The modified polypeptide of claim 2, wherein said heptad repeat domain comprises the formula:
-TW—WDR—I—Y—I-LI-Q-QEK-E-L-EL, or conservative amino acid substitutions thereof and wherein “-” can be any amino acid (SEQ ID NO: 45).

### Claim at position 8

8-9. (canceled)

### Claim 10 (depends on 2)

The modified polypeptide of claim 2, wherein said hydrocarbon staple is positioned so as to link amino acid residue i and i+3, amino acid residues i and i+4, or amino acid residues i and i+7.

### Claim at position 10

11-12. (canceled)

### Claim 13 (depends on 1)

The modified polypeptide of claim 1, wherein said modified polypeptide has at least 10%, 20%, 30%, 50%, 60%, 70%, 80%, or 90% alpha helicity in aqueous solution as determined by circular dichroism.

### Claim at position 12

14-20. (canceled)

### Claim 21 (depends on 1)

The modified polypeptide of claim 1, wherein said heptad repeat domain is an HIV-1 gp41 heptad repeat domain 1, an HIV-1 gp41 heptad repeat domain 2, an HIV-2 gp41 heptad repeat domain 1, an HIV-2 gp41 heptad repeat domain 2, an SIV gp41 heptad repeat domain 1, or an SIV gp41 heptad repeat domain 2.

### Claim at position 14

22-24. (canceled)

### Claim 25 (depends on 1)

The modified polypeptide of claim 1, wherein said modified polypeptide is a chimera.

### Claim 26 (depends on 25)

The modified polypeptide of claim 25, wherein said chimera has the amino acid sequence of WQEWEQKITALLEQAQIQQEKNEYELQKLDKWASLWEWF (SEQ ID NO: 46).

### Claim at position 17

27-30. (canceled)

### Claim 31 (depends on 1)

The modified polypeptide of claim 1, wherein said heptad repeat domain forms an alpha helix and is 30% or more identical to the amino acid sequence selected from the group consisting of:
(SEQ ID NO: 1)
YTSLIHSLIEESQNQQEKNEQELLELDKWASLWNWF,
(SEQ ID NO: 2)
NNLLRAIEAQQHLLQLTVWGIKQLQARILAVERYLQDQ,
(SEQ ID NO: 3)
BTWBEWDREINNYTSLIHSL,
(SEQ ID NO: 13)
MTWMEWDREINNYTSLIHSLIEESQNQQEKNEQELLE,
(SEQ ID NO: 58)
YTHIIYSLIEQSQNQQEKNEQELLALDKWASLWNWF,
and
(SEQ ID NO: 59)
MTMKWEREIDNYTHIIYSLIEQSQNQQEKNEQELLA.

### Claim at position 19

32-34. (canceled)

### Claim 35 (depends on 2)

The modified polypeptide of claim 2, wherein said heptad repeat domain has the formula:
BTW*BEWD*REINNYTSLIHSL, wherein * identifies the amino acid residues which are linked by the hydrocarbon staple and B is methionine or norleucine (SEQ ID NO: 47), or BTWBEWDREINNYTSLIHSLIEESQNQQ*EKNE*QELLE, wherein * identifies the amino acid residues which are linked by the hydrocarbon staple and B is methionine or norleucine (SEQ ID NO: 48).

### Claim 36

(canceled)

### Claim 37 (depends on 2)

The modified polypeptide of claim 2, wherein said modified polypeptide has a formula selected from the group consisting of:
(SEQ ID NO: 15)
BTWXEWDXEINNYTSLIHSL,
(SEQ ID NO: 16)
BTWBEWDREINNYTSLIHSLIEESQNQQXKNEXELLE,
(SEQ ID NO: 17)
BTWBXWDRXINNYTSL,
(SEQ ID NO: 18)
BTWBEWDREINNYTSLIHSLIEXSQNXQEKNEQELLE,
(SEQ ID NO: 19)
BTWBXWDRXINNYTSLIHSLIEESQNQQEKNEQELLE,
(SEQ ID NO: 20)
BTWBXWDRXINNYTSLIHSLIEXSQNXQEKNEQELLE,
(SEQ ID NO: 21)
BTWBEWDREINNYTSLIHSLIEESQNQQXKNEXELLE,
(SEQ ID NO: 22)
BTWBXWDRXINNYTSLIHSLIEESQNQQXKNEXELLE,
(SEQ ID NO: 23)
BTWBEWDXEINXYTSLIHSLIEESQNQQXKNEXELLE,
(SEQ ID NO: 24)
BTWBEWDREINXYTSXIHSLIEESQNQQXKNEXELLE,
(SEQ ID NO: 25)
BTWBEWDREINNYTSXIHSXIEESQNQQXKNEXELLE,
(SEQ ID NO: 26)
BTWBXWDRXINNYTSXIHSXIEESQNQQXKNEXELLE,
(SEQ ID NO: 27)
YTSXIHSXIEESQNQQEKNEQELLELDKWASLWNWF,
(SEQ ID NO: 28)
YTSLIXSLIXESQNQQEKNEQELLELDKWASLWNWF,
(SEQ ID NO: 29)
YTSLIHSLIEXSQNXQEKNEQELLELDKWASLWNWF,
(SEQ ID NO: 30)
YTSLIHSLIEESQNQQXKNEXELLELDKWASLWNWF,
(SEQ ID NO: 31)
YTSLIHSLIEESQNQQEXNEQXLLELDKWASLWNWF,
(SEQ ID NO: 32)
YTSLIHSLIEESQNQQEKNEQXLLEXDKWASLWNWF,
(SEQ ID NO: 33)
YTSLIHSLIEESQNQQEKNEQELLELDXWASXWNWF,
(SEQ ID NO: 34)
YTSLIHSLIEESQNQQEKNEQELLELDKWXSLWXWF,
(SEQ ID NO: 35)
YTSLIHSLIEXSQNXQEKNEQXLLEXDKWASLWNWF,
(SEQ ID NO: 36)
YTSXIHSXIEESQNQQEKNEQELLELDKWXSLWXWF,
(SEQ ID NO: 37)
YTSLIHSLIEESQNQQXKNEXELLELDKWXSLWXWF,
(SEQ ID NO: 38)
YTSXIHSXIEESQNQQXKNEXELLELDKWASLWNWF,
(SEQ ID NO: 39)
YTSXIHSXIEESQNQQEKNEQELLELDXWASXWNWF,
(SEQ ID NO: 40)
YTSLIHSLIEXSQNXQEKNEQELLELDXWASXWNWF,
(SEQ ID NO: 41)
YTSXIHSXIEESQNQQXKNEXELLELDXWASXWNWF,
(SEQ ID NO: 42)
BTWBXWDRXINNYTSLIHSLIEESQNQXEKNXQELLE,
and
(SEQ ID NO: 43)
BTWBXWDRXINNYTSLIHSLIEESQNXQEKXEQELLE;
wherein X is any amino acid and further identifies the amino acid residues which are linked by a hydrocarbon staple, and B is methionine or norleucine.

### Claim 38

A modified polypeptide comprising a stabilized viral alpha helix heptad repeat-analog domain.

### Claim 39 (depends on 38)

The modified polypeptide of claim 38, wherein said stabilized viral alpha helix heptad repeat-analog domain is derived from a virus selected from a respiratory syncytial virus, a parainfluenza virus, an influenza virus, a paramyxovirus, an orthomyxovirus, a coronavirus, and a filovirus.

### Claim 40 (depends on 39)

The modified polypeptide of claim 39, wherein said modified polypeptide forms an alpha-helix and comprises an amino acid sequence which is 30% or more identical to the amino acid sequence selected from the group consisting of:
(SEQ ID NO: 4)
YTSVITIELSNIKENKCNGTDAKVKLIKQELDKYKNAVTELQLLMQST,
(SEQ ID NO: 5)
FYDPLVFPSDEFDASISQVNEKINQSLAFIRKSDELL,
(SEQ ID NO: 6)
ALGVATSAQITAAVALVEAKQARSDIEKLKEAIR,
(SEQ ID NO: 7)
NVLYENQKQIANQFNKAISQIQESLTTTSTALGKLQDVVNQNAQAL
NTLVKQLSSNFGAISSVLNDILSRLDKVEAE,
(SEQ ID NO: 8)
TSPDVDFGDISGINASVVNIQKEIDRLNEVAKNLNESLIDLQELGKY,
(SEQ ID NO: 9)
DGLICGLRQLANETTQALQLFLRATTELRTFSILNRKAIDFLL,
SEQ ID NO: 10)
DWTKNITDKIDQIIHDFVDKTLPD,
(SEQ ID NO: 11)
SGIAVSKVLHLEGEVNKIKNALLSTNKAVVSLSNGVSVLTSKVLDLKS
YINNQLLPI-,
and
(SEQ ID NO: 12)
PIINYYDPLVFPSDEFDASISQVNEKINQSLAFIRRSDELLHNVNTGK
STTNIM.

### Claim at position 26

41-51. (canceled)

### Claim 52

A modified polypeptide
having an amino acid sequence which is 30% or more identical to an amino acid sequence selected from the group consisting of SEQ ID NOs: 1-43.

### Claim at position 28

53-56. (canceled)

### Claim 57 (depends on 52)

A composition comprising the modified polypeptide of claim 52.

### Claim 58 (depends on 57)

The composition of claim 57, wherein said composition is a pharmaceutical composition.

### Claim at position 31

59-60. (canceled)

### Claim 61 (depends on 57)

A kit comprising the composition of claim 57 and instructions for use.

### Claim 62 (depends on 52)

A method for inhibiting transmission of HIV, RSV, parainfluenza virus, influenza virus, or paramyxovirus to a cell comprising contacting the virus in the presence of the cell with an effective dose of the modified polypeptide of claim 52, so that the infection of the cell by the virus is inhibited.

### Claim 63 (depends on 62)

The method of claim 62, wherein said modified polypeptide is in a pharmaceutical composition.

### Claim at position 35

64-79. (canceled)

### Claim 80 (depends on 52)

An antibody to the modified polypeptide of claim 52.

### Claim at position 37

81-85. (canceled)

### Claim 86 (depends on 80)

A method for inhibiting transmission of HIV, RSV, parainfluenza virus, influenza virus, or paramyxovirus to a cell comprising contacting the virus in the presence of the cell with an effective dose of the antibody of claim 80, so that the infection of the cell by the virus is inhibited.