# US 2013/0157931 A1 · Mitochondrial penetrating peptides as carriers for antimicrobials

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- Number: US 2013/0157931 A1
- Document ID: US20130157931A1
- Status: Published application
- Kind: A1
- Application number: 13/700,988
- Filed: 2011-05-27
- Published: 2013-06-20
- Earliest claimed: 2010-05-30
- Assignees: The Governing Council of the University of Toronto
- Inventors: Shana Kelley; Mark Pereira
- Web page: https://patentgrep.com/patent/US20130157931A1

## CPC

- A61K 47/64: Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent (peptidic linkers A61K47/65)
- A61K 38/08: Peptides having 5 to 11 amino acids {(A61K38/043 - A61K38/046 take precedence)}
- A61K 47/645: {Polycationic or polyanionic oligopeptides, polypeptides or polyamino acids, e.g. polylysine, polyarginine, polyglutamic acid or peptide TAT}
- A61P 31/00: Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P 31/04: Antibacterial agents
- A61P 31/12: Antivirals
- C07K 7/06: having 5 to 11 amino acids
- 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
- 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

There is described herein compounds comprising a mitochondrial penetrating peptide (MPP) conjugated to an antimicrobial, and their method of use.

## Claims

### Claim 1

A compound comprising a mitochondrial penetrating peptide (MPP) conjugated to an antimicrobial, preferably an antibacterial.

### Claim 2 (depends on 1)

The compound of claim 1, wherein the antimicrobial is an antimetabolite, glycolysis inhibitor or a reverse transcriptase inhibitor.

### Claim 3 (depends on 2)

The compound of claim 2, wherein the antimicrobial is an antimetabolite that is a pyrimidine analogue, purine analog or antifolate.

### Claim 4 (depends on 2)

The compound of claim 2, wherein the antimicrobial is an antimetabolite that is 5-fluorouracil, gemcitabine, azathioprine, mecaptopurine, methotrexate, raltritrexed or pemetrexed.

### Claim 5 (depends on 2)

The compound of claim 2, wherein the antimicrobial is methotrexate, preferably MtxA.

### Claim 6 (depends on 2)

The compound of claim 2, wherein the antimicrobial is a glycolysis inhibitor that is a hexokinase inhibitor, lactate dehydrogenase inhibitor or glucose-6-phosphate dehydrogenase inhibitor, preferably 2-deoxyglucose, 3-bromopyruvate, oxamate or 6-aminonicotinamide.

### Claim 7 (depends on 2)

The compound of claim 2, wherein the antimicrobial is an antiretroviral, preferably azidothymidine.

### Claim 8 (depends on 1)

The compound of claim 1, wherein the antimicrobial has a target in human cells that resides in the cytoplasm.

### Claim 9 (depends on 1)

The compound of claim 1, wherein the MPP is both lipophilic and cationic.

### Claim 10 (depends on 1)

The compound of claim 1, wherein the MPP can traverse the inner membrane of the mitochondria.

### Claim 11 (depends on 10)

The compound of claim 10, wherein the MPP crosses the membrane in a potential dependent manner.

### Claim 12 (depends on 1)

The compound of claim 1, wherein the MPP comprises charged amino acids and hydrophobic amino acids.

### Claim 13 (depends on 12)

The compound of claim 12, wherein the charged amino acids are selected from lysine and arginine.

### Claim 14 (depends on 1)

The compound of claim 1, wherein the hydrophobic amino acids are selected from phenylalanine (F), cyclohexylalanine (Fx), aminooctaarginine (Hex), diphenylalanine (F2) and (1-naphthyl)-L-alanine (Nap).

### Claim 15 (depends on 1)

The compound of claim 1, wherein the MPP comprises amino acid residues modified to provide intracellular stability.

### Claim 16 (depends on 15)

The compound of claim 15, wherein the MPP comprises d-stereoisomers.

### Claim 17 (depends on 15)

The compound of claim 15, wherein the MPP comprises an amide terminus.

### Claim 18 (depends on 1)

The compound of claim 1, wherein the MPP comprises a charge of +3 and a log P value of at least about −1.7.

### Claim 19 (depends on 1)

The compound of claim 1, wherein the MPP comprises a charge of +5 and a log P value of at least about −2.5.

### Claim 20 (depends on 1)

The compound of claim 1, wherein the MPP is any one of SEQ ID NOs. 1-7.

### Claim 21 (depends on 1)

The compound of claim 1, wherein the antimicrobial is conjugated to the N-terminus of the MPP.

### Claim 22 (depends on 1)

The compound of claim 1 being Mtx-Fxr3 or MtxA-Fxr3.

### Claim 23

(canceled)

### Claim 24 (depends on 1)

A pharmaceutical composition comprising the compound of claim 1 and a pharmaceutically acceptable carrier.

### Claim 25 (depends on 1)

A library of compounds comprising a plurality of compounds of claim 1.

### Claim 26 (depends on 23)

A method of treating an infection by a microbe, preferably bacteria, further preferably Gram-positive bacteria, in a subject comprising administering to the subject a therapeutically effect amount of the composition of claim 23.

### Claim at position 27

-28. (canceled)

### Claim 29

A method of optimizing delivery of an antimicrobial to a microbe, preferably bacteria, further preferably Gram-positive bacteria, comprising conjugating the antimicrobial with a MPP.

### Claim 30

A peptide consisting of SEQ ID NO. 7.