# US 10,118,948 B2 · Antimicrobial peptides, pharmaceutical compositions, and methods of use thereof

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- Number: US 10,118,948 B2
- Document ID: US10118948B2
- Status: Granted
- Kind: B2
- Application number: 15/371,683
- Filed: 2016-12-07
- Published: 2017-05-25
- Granted: 2018-11-06
- Earliest claimed: 2014-06-09
- Assignees: The United States of America, as represented by the Secretary, Department of Health and Human Services
- Applicants: The United States of America, as Represented by the Secretary, Department of Health and Human Services
- Inventors: Jie Zheng; Ann Marie Knolhoff; Eric Wayne Brown; Timothy Ray Croley
- Web page: https://patentgrep.com/patent/US10118948B2

## CPC

- C07K 7/56: the cyclisation not occurring through 2,4-diamino-butanoic acid
- A01N 37/46: N-acyl derivatives
- A61K 38/10: Peptides having 12 to 20 amino acids {(A61K38/043 - A61K38/046 take precedence)}
- A61K 47/542: {Carboxylic acids, e.g. a fatty acid or an amino acid}
- A61P 31/04: Antibacterial agents
- C07K 7/08: having 12 to 20 amino acids (gastrins C07K14/595; somatostatins C07K14/655; melanotropins C07K14/68)
- C07K 7/64: Cyclic peptides containing only normal peptide links
- C07K 19/00: Hybrid peptides {, i.e. peptides covalently bound to nucleic acids, or non-covalently bound protein-protein complexes}
- 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)
- Y02A 50/30: Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
- 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)
- A01N: PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF (preservation of food or foodstuff A23); BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES (preparations for medical, dental or toiletry purposes which kill or prevent the growth or proliferation of unwanted organisms A61K); PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
- 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
- Y02A: TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE

## Abstract

Disclosed herein are novel antimicrobial peptides, pharmaceutical compositions containing the peptides, and methods of use of the peptides to inhibit the growth or proliferation of microbes. The antimicrobial peptides are particularly useful to treat infections of dangerous gram positive organisms such as MRSA and VRSA.

## Claims

### Claim 1

A method of inhibiting growth or proliferation of a bacterium, comprising contacting the bacterium with an effective amount of a peptide comprising the amino acid sequence:
Xaa1-Val2-Thr3-D-Orn4-Ser5-Xaa6-Xaa7-D-Ser8-Ile9-Pro10-Ile11-Pro12-Ile13,
wherein Xaa6 is Tyr or Phe, wherein Xaa1 and Xaa7 are each independently L-Lys D-Lys or D-Orn,
and wherein the peptide optionally comprises a saturated or unsaturated, substituted or unsubstituted, linear or branched, C4-C20 fatty acid group, or a saturated or unsaturated, linear or branched C4-C20 ester covalently linked to Xaa1,
thereby inhibiting the growth or proliferation of the bacterium.

### Claim 2 (depends on 1)

The method of claim 1, wherein the bacterium is a Gram positive bacterium.

### Claim 3 (depends on 1)

The method of claim 1, wherein the infection bacterium is Enterococcus (E.) faecalis, methicillin resistant Staphylococcus aureus (MRSA), vancomycin resistant Staphylococcus aureus (VRSA), or carbapenem resistant Enterobacteriaceae (CRE).

### Claim 4 (depends on 1)

The method of claim 1, wherein the peptide comprises the saturated or unsaturated, substituted or unsubstituted, linear or branched C4-C20 fatty acid group covalently linked to Xaa1.

### Claim 5 (depends on 1)

The method of claim 1, wherein the fatty acid group has the formula C10H19O, C11H21O, C12H23O, C13H25O, C14H27O, or C15H29O.

### Claim 6 (depends on 5)

The method of claim 5, wherein the peptide comprises the sequence: D-Orn1-Val2-Thr3-D-Orn4-Ser5-Tyr6-Lys7-D-Ser8-Ile9-Pro10-Ile11-Pro12-Ile13.

### Claim 7 (depends on 1)

The method of claim 1, wherein Xaa1 is D-Orn and-Xaa7 is L-Lys or D-Lys.

### Claim 8 (depends on 1)

The method of claim 1, wherein the bacterium is a Gram negative bacterium.

### Claim 9

A method of inhibiting growth or proliferation of a bacterium in a subject in need thereof, the method comprising administering to the subject a composition comprising a peptide and a pharmaceutically acceptable carrier, wherein the peptide comprises the amino acid sequence:
Xaa1-Val2-Thr3-D-Orn4-Ser5-Xaa6-Xaa7-D-Ser8-Ile9-Pro10-Ile11-Pro12-Ile13,
wherein Xaa6 is Tyr or Phe, wherein Xaa1 and Xaa7 are each independently L-Lys, D-Lys or D-Orn,
wherein the peptide optionally comprises a saturated or unsaturated, substituted or unsubstituted, linear or branched, C4-C20 fatty acid group, or a saturated or unsaturated, linear or branched C4-C20 ester covalently linked to Xaa1,
and wherein the composition is administered in an amount effective to inhibit growth or proliferation of the bacterium.

### Claim 10 (depends on 9)

The method of claim 9, wherein the bacterium is a Gram positive bacterium.

### Claim 11 (depends on 9)

The method of claim 9, wherein the subject is a mammal.

### Claim 12 (depends on 11)

The method of claim 11, wherein the subject is a human subject.

### Claim 13 (depends on 9)

The method of claim 9, wherein the peptide comprises the saturated or unsaturated, substituted or unsubstituted, linear or branched C4-C20 fatty acid group, or the saturated or unsaturated, linear or branched C4-C20 ester covalently linked to Xaa1.

### Claim 14 (depends on 13)

The method of claim 13, wherein Xaa1 is D-Orn.

### Claim 15 (depends on 14)

The method of claim 14, wherein the peptide comprises the saturated or unsaturated, substituted or unsubstituted, linear or branched C4-C20 fatty acid group covalently linked to Xaa1.

### Claim 16 (depends on 15)

The method of claim 15, wherein the fatty acid group has the formula C10H19O, C11H21O, C12H23O, C13H25O, C14H27O, or C15H29O.

### Claim 17 (depends on 16)

The method of claim 16, wherein Xaa6 of the peptide is Phe.

### Claim 18 (depends on 9)

The method of claim 9, wherein Xaa6 of the peptide is Tyr and the peptide comprises the saturated or unsaturated, linear or branched C4-C20 ester covalently linked to Xaa1.

### Claim 19 (depends on 18)

The method of claim 18, wherein the ester has the formula C10H19O2, C11H21O2, C12H23O2, C13H25O2, C14H27O2, or C15H29O2.

### Claim 20 (depends on 9)

The method of claim 9, wherein the peptide is cyclized through a bond between Thr3 and Ile13.

### Claim 21 (depends on 9)

The method of claim 9, wherein Xaa7 of the peptide is D-Lys or L-Lys.

### Claim 22 (depends on 9)

The method of claim 9, wherein Xaa1 is D-Orn and Xaa7 is L-Lys or D-Lys.

### Claim 23 (depends on 22)

The method of claim 22, wherein the composition further comprises a second peptide, and wherein the second peptide comprises the sequence: D-Orn1-Val2-Thr3-D-Orn4-Ser5-Tyr6-D-Lys7-D-Ser8-Ile9-Pro10-Ile11-Pro12-Ile13.

### Claim 24 (depends on 22)

The method of claim 22, wherein the bacterium is a Gram positive bacterium.

### Claim 25 (depends on 9)

The method of claim 9, wherein the peptide is covalently bound to C13H25O.

### Claim 26 (depends on 9)

The method of claim 9, wherein the bacterium is a vancomycin resistant enterococci (VRE).

### Claim 27

A method of inhibiting growth or proliferation of a Gram positive bacterium in a subject in need thereof, the method comprising contacting the bacterium with an effective amount of a peptide comprising the amino acid sequence D-Orn1-Val2-Thr3-D-Orn4-Ser5-Tyr6-Lys7-D-Ser8-Ile9-Pro10-Ile11-Pro12-Ile13, wherein the peptide is covalently linked to C13H25O, thereby inhibiting the growth or proliferation of the bacterium.

### Claim 28 (depends on 27)

The method of claim 27, wherein the bacterium is Enterococcus (E.) faecalis.

### Claim 29 (depends on 27)

The method of claim 27, further comprising contacting the Gram positive bacterium with an effective amount of a second peptide, wherein the second peptide comprises the sequence: D-Orn1-Val2-Thr3-D-Orn4-Ser5-Tyr6-D-Lys7-D-Ser8-Ile9-Pro10-Ile11-Pro12-Ile13.