# US 8,785,399 B2 · Antibacterial peptides

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- Number: US 8,785,399 B2
- Document ID: US8785399B2
- Status: Granted
- Kind: B2
- Application number: 12/995,802
- Filed: 2009-06-02
- Published: 2011-03-31
- Granted: 2014-07-22
- Earliest claimed: 2008-06-02
- Assignees: Spiderbiotech S.R.A.
- Applicants: Andrea Giuliani; Giovanna Pirri; Silvia Fabiole Nicoletto
- Inventors: Andrea Giuliani; Giovanna Pirri; Silvia Fabiole Nicoletto
- Web page: https://patentgrep.com/patent/US8785399B2

## CPC

- C07K 14/4723: {Cationic antimicrobial peptides, e.g. defensins}
- A23B 2/762: Organic compounds containing nitrogen
- A61K 8/64: Proteins; Peptides; Derivatives or degradation products thereof
- A61P 1/02: Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
- A61P 27/04: Artificial tears; Irrigation solutions
- A61P 31/00: Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P 31/04: Antibacterial agents
- A61P 31/10: Antimycotics
- A61P 33/00: Antiparasitic agents
- A61Q 11/00: Preparations for care of the teeth, of the oral cavity or of dentures; Dentifrices, e.g. toothpastes; Mouth rinses
- A61Q 19/00: Preparations for care of the skin
- A23V 2002/00: Food compositions, function of food ingredients or processes for food or foodstuffs
- 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)
- A61K 2800/524: Preservatives
- 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)
- A23B: PRESERVATION OF FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES; CHEMICAL RIPENING OF FRUIT OR VEGETABLES
- 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
- A61Q: SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
- A23V: INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION

## Abstract

The present invention relates to monomeric and multimeric peptidic compounds which have antimicrobial activity, particularly against Gram-positive and Gram-negative bacteria. Further, the present invention refers to compositions comprising said peptidic compounds for medical use, for use as a disinfectant and/or detergent or for use as a preservative.

## Claims

### Claim 1

A peptidic compound having a length of up to 35 amino acid residues comprising an amino acid sequence represented by the general formula (Ib):
Z-[K]n-K-I-R-V-R-L-S-A
(SEQ ID NO: 26)
wherein K is a lysine or another amino acid residue with a positively charged side chain,
I is an isoleucine,
R is an arginine or an amino acid residue with an N-alkyl substituted guanidine side chain,
V is a valine,
S is a serine,
A is an alanine,
L is a leucine,
wherein one of the amino acid residues K, I, R, L, V and S may be replaced by an alanine,
Z is the N-terminal group of the peptidic compound which comprises at least one amino acid residue and is selected from
(i) an aromatic amino acid residue or a di-, tri- or tetrapeptidyl group comprising at least one aromatic amino acid residue, wherein the aromatic amino acid residue is particularly selected from tryptophane, N-methyltryptophane, phenylalanine, β-phenylalanine, naphthylalanine, β-naphthylalanine, β-diphenylalanine,β-(4,4′-biphenyl)alanine, β-anthracen-9-ylalanine and β-indol-3-ylalanine,
(ii) a branched aliphatic amino acid residue or a di-, tri-, tetrapeptidyl group comprising at least one aliphatic amino acid residue, wherein the aliphatic residue is α-amino acid residue comprising a branched aliphatic side chain of at least 3 C-atoms,
(iii) combinations of any one of (i)-(ii), and n is 0 or 1,
and wherein the peptidic compound comprises L- and/or D-amino acid residue building blocks, which are selected from α-amino carboxylic acids, β-amino carboxylic acids, or ω-amino carboxylic acids.

### Claim 2 (depends on 1)

The peptidic compound according to claim 1, wherein the N-terminal group Z is selected from Ar, Ar-Q, X-Q-Ar, Acetyl-Q-Ar, G-Q-Ar, and pyrE-Ar, wherein Ar is an aromatic amino acid residue, and wherein X is an amino acid residue different from Q.

### Claim 3

A peptidic compound having the amino acid sequence selected from the group consisting of:
WKKIRVRLSA
(SEQ ID NO: 6)
pyrEWKIRVRLSA
(SEQ ID NO: 27)
GQWKIRVRLSA.
(SEQ ID NO: 14)
Acetyl-QWKIRVRLSA
(SEQ ID NO: 12)
Aoa-QWKIRVRLSA
(SEQ ID NO: 16)
and
(GQWKIRVRLSA)2 K-β-Ala
(SEQ ID NO: 19)
wherein pryE is a pyroglutamic acid residue, Aoa is an 8-amino octanoic acid residue, β-Ala is a β-alanine residue and wherein said peptides are optionally amidated at their C-termini.

### Claim 4 (depends on 1)

The peptidic compound according to claim 1, having a length of up to 15 amino acid residues.

### Claim 5 (depends on 1)

The peptidic compound according to claim 1, has a linear or cyclic form.

### Claim 6 (depends on 1)

A multimeric compound comprising a plurality of said peptidic compound as defined in claim 1.

### Claim 7 (depends on 6)

The multimeric compound of claim 6 which is multimerized on a matrix, particularly selected from the group consisting of poly (N-alkyl(meth)acrylamide), poly (N,N-dialkyl(meth)acrylamide), polymelamine, dextrane, cyclodextrine, polyethyleneglycol, and polyvinylpyrrolidone.

### Claim 8 (depends on 6)

The multimeric compound of claim 6, wherein said multimetric compound has a branched, particularly a dendritic structure.

### Claim 9 (depends on 1, 7)

The multimeric compound of claim 7 selected from the group consisting of:
(i) R—(Y1—R)m—Y1-(R)m′ (IIa)
wherein R is a peptidic compound as defined in claim 1,
Y1 is a covalent bond or a bifunctional linker, and m is 0 or a positive whole number, and m′ is 0 or 1,
(ii) [[(R)n1Y1′]n2]Y2 (IIb)
wherein R is a peptidic compound as defined in claim 1,
Y1′is in each case independently a linker having a functionality of at least 3, and
Y2 is a linker having a functionality of at least 2, and
n1 and n2 in each case independently are a whole number of at least 2, and
(iii) {[[(R)n1 Yl′]n2]Y2 ′}n3Y3 (IIc)
wherein R is a peptidic compound as defined in claim 1,
Y1′and Y2′are in each case independent linkers having a functionality of at least 3,
Y3 is a linker having a functionality of at least 2, and
n1, n2 and n3 are in each case independently whole numbers of at least 2.

### Claim 10 (depends on 9)

The multimeric compound of claim 9, wherein said multimeric compound comprises at least one modification selected from the group consisting of a lipid, amide, ester, acyl, and alkyl moiety attached thereto.

### Claim 11 (depends on 10)

The multimeric compound of claim 10, comprising at least one lipid moiety comprising at least one amino carboxylic acid comprising a linear or cyclic, saturated mono- or polyunsaturated hydrocarbon group having 3 to 25 C-atoms.

### Claim 12 (depends on 9)

The multimeric compound of claim 9 having activity against pathogenic organisms selected from prokaryotic organisms.

### Claim 13 (depends on 9)

The multimeric compound of claim 9 having anti-bacterial activity.

### Claim 14 (depends on 9)

A composition for medical use comprising at least one multimeric compound as defined in claim 9 together with pharmaceutically acceptable carriers, diluents, or adjuvants.

### Claim 15 (depends on 1)

The composition of claim 1 being in a pharmaceutical dosage form selected from the group consisting of solids, liquids, gels and combinations thereof.

### Claim 16 (depends on 1)

A disinfectant or detergent comprising at least one compound as defined in claim 1.

### Claim 17 (depends on 1)

A preservative comprising at least one compound as defined in claim 1.

### Claim 18 (depends on 17)

The compound of claim 17 as a preservative for medical, cosmetic or food products.

### Claim 19 (depends on 17)

The compound of claim 17 for decreasing growth or proliferation of biofilm embedded microorganisms.

### Claim 20 (depends on 1)

A veterinary composition comprising at least one peptidic compound as defined in claim 1.

### Claim 21 (depends on 6)

A disinfectant or detergent comprising at least one compound as defined in claim 6.

### Claim 22 (depends on 6)

A preservative comprising at least one compound as defined in claim 6.

### Claim 23 (depends on 6)

A veterinary composition comprising at least one multimeric compound as defined in claim 6.

### Claim 24 (depends on 9)

The multimeric compound of claim 9, wherein Y1 is a covalent bond or a bifunctional linker selected from the group consisting of a dialcohol, a dicarboxylic acid, a diamine, an amino acid, a hydroxy carboxylic acid, and a diisocyanate.

### Claim 25 (depends on 24)

The multimeric compound of claim 24, wherein the dialcohol is propylene glycol, the dicarboxylic acid is succinic acid, the diamine is ethylene diamine.

### Claim 26 (depends on 9)

The multimeric compound of claim 9, wherein Y1′ is in each case independently a linker having a functionality of at least 3 which is a trifunctional amino acid selected from the group consisting of lysine, ornithine, nor-lysine, aminoalanine, aspartic acid, and glutamic acid.

### Claim 27 (depends on 9)

The multimeric compound of claim 9, wherein Y1′ and Y2′ are in each case independent linkers having a functionality of at least 3 which is a trifunctional amino acid selected from the group consisting of lysine, ornithine, nor-lysine, aminoalanine, aspartic acid, and glutamic acid.

### Claim 28 (depends on 11)

The multimeric compound of claim 11, wherein the at least one amino carboxylic acid is selected from 5-amino valeric acid, 8-amino octanoic acid, and 2-amino decanoic acid.

### Claim 29 (depends on 11)

The multimeric compound of claim 11, wherein the at least one amino carboxylic acid is attached to the N- or C-terminus of the multimeric compound.

### Claim 30 (depends on 1)

The multimeric compound of claim 1, wherein said amino acid residue K, I, R, L, V or S is an L-amino acid.