# US 10,308,686 B2 · Gamma-AApeptides with potent and broad-spectrum antimicrobial activity

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- Number: US 10,308,686 B2
- Document ID: US10308686B2
- Status: Granted
- Kind: B2
- Application number: 16/205,500
- Filed: 2018-11-30
- Published: 2019-04-04
- Granted: 2019-06-04
- Earliest claimed: 2012-01-23
- Assignees: University of South Florida
- Applicants: Jianfeng Cai; Youhong Niu; Haifan Wu; Shruti Padhee
- Inventors: Jianfeng Cai; Youhong Niu; Haifan Wu; Shruti Padhee
- Web page: https://patentgrep.com/patent/US10308686B2

## CPC

- C07K 7/56: the cyclisation not occurring through 2,4-diamino-butanoic acid
- A61K 38/08: Peptides having 5 to 11 amino acids {(A61K38/043 - A61K38/046 take precedence)}
- A61K 38/12: Cyclic peptides {, e.g. bacitracins; Polymyxins; Gramicidins S, C; Tyrocidins A, B or C (A61K38/043 - A61K38/046 take precedence)}
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61K 47/543: {Lipids, e.g. triglycerides; Polyamines, e.g. spermine or spermidine}
- A61K 49/0056: {Peptides, proteins, polyamino acids}
- A61P 31/04: Antibacterial agents
- C07K 1/10: using coupling agents {(C07K1/006 takes precedence)}
- C07K 1/16: by chromatography
- C07K 7/06: having 5 to 11 amino acids
- C07K 7/64: Cyclic peptides containing only normal peptide links
- G01N 33/569: for microorganisms, e.g. protozoa, bacteria, viruses
- 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)
- 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
- G01N: INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES (measuring or testing apparatus or processes other than immunoassay, involving enzymes or microorganisms C12M, C12Q)
- Y02A: TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE

## Abstract

The present invention is directed to a novel class of antimicrobial agents called γ-AApeptides. The current invention provides various categories of γ-AApeptides, for example, linear γ-AApeptides, cyclic γ-AApeptides, and lipidated γ-AApeptides. γ-AApeptides of the current invention are designed to exert antimicrobial activity while being stable and non-toxic. γ-AApeptides also do not appear to lead to the development of microbial resistance in treated microorganisms. Thus, the disclosed γ-AApeptides can be used for the treatment of various medical conditions associated with pathogenic microorganisms.

## Claims

### Claim 1

A γ-AApeptide prepared by a process comprising the steps of:
reacting an Fmoc protected amino aldehyde comprising:
wherein R1 is a straight or branched chain C1 to C 10 alkyl group, —CH2—CH2—S—CH3; a —(CH2)1-5-aryl group, or an —(CH2)1-5-heteroaryl group, and wherein the alkyl group, the aryl group or the heteroaryl group can be substituted or unsubstituted,
with glycine benzyl ester comprising:
to form a secondary amine comprising:
reacting
with a substituted or unsubstituted aryl, substituted or unsubstituted 5-membered heterocyclic ring of which one to four member(s) may be heteroatoms, γ-Boc-amino butyric acid, di-Boc-guanidinopropionic acid, mono-allyl succinate or substituted or unsubstituted alkanoic acid followed by hydrogenation to form γ-AApeptide building blocks comprising:
wherein R2 is substituted or unsubstituted aryl, substituted or unsubstituted 5-membered heterocyclic ring of which one to four member(s) may be heteroatoms, amino-propyl, allyl-propyl, or substituted or unsubstituted alkyl;
attaching a first γ-AApeptide building block to a solid support;
coupling the first γ-AApeptide building block with a second γ-AApeptide building block;
repeating the coupling step to form the γ-AApeptide attached to the solid support; and
cleaving the γ-AApeptide attached to the solid support from the solid support to form the γ-AApeptide.

### Claim 2 (depends on 1)

The γ-AApeptide prepared by the process of claim 1, wherein the solid support is a Rink amide resin or a Knorr resin.

### Claim 3 (depends on 1)

The γ-AApeptide prepared by the process of claim 1, wherein R1 is a methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, s-butyl or t-butyl group.

### Claim 4 (depends on 1)

The γ-AApeptide prepared by the process of claim 1, wherein the repeating step is performed to couple between 5 and 50 γ-AApeptide building blocks.

### Claim 5 (depends on 1)

The γ-AApeptide prepared by the process of claim 1, wherein the step of reacting an Fmoc protected amino aldehyde with glycine benzyl ester further comprises sodium cyanoborohydride.

### Claim 6 (depends on 1)

The γ-AApeptide prepared by the process of claim 1, wherein the step of reacting
with the substituted or unsubstituted aryl, substituted or unsubstituted 5-membered heterocyclic ring of which one to four member(s) may be heteroatoms, γ-Boc-amino butyric acid, di-Boc-guanidinopropionic acid, mono-allyl succinate or substituted or unsubstituted alkanoic acid further comprises diisopropylcarbodiimide, 3-4-dihydro-3-hydroxy-4-oxo-1-2-3-benzotriazine, and dimethylformamide.

### Claim 7 (depends on 1)

The γ-AApeptide prepared by the process of claim 1, wherein hydrogenation to form γ-AApeptide building blocks comprises a palladium on carbon catalyst and molecular hydrogen.

### Claim 8 (depends on 1)

The γ-AApeptide prepared by the process of claim 1, wherein attaching a first γ-AApeptide building block to a solid support further comprises N,N′-Diisopropylearbodiimide and oxohydroxybenzotriazole.

### Claim 9 (depends on 1)

The γ-AApeptide prepared by the process of claim 1, wherein coupling the first γ-AApeptide building block with a second γ-AApeptide building block further comprises N,N′-Diisopropylcarbodiimide and oxohydroxybenzotriazole.

### Claim 10 (depends on 1)

The γ-AApeptide prepared by the process of claim 1, wherein coupling the first γ-AApeptide building block with a second γ-AApeptide building block further comprises benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate.

### Claim 11 (depends on 1)

The γ-AApeptide prepared by the process of claim 1, wherein coupling the first γ-AApeptide building block with a second γ-AApeptide building block further comprises 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate and hydroxybenzotriazole.

### Claim 12 (depends on 1)

The γ-AApeptide prepared by the process of claim 1, wherein cleaving the γ-AApeptide attached to the solid support from the solid support to form the γ-AApeptide further comprises trifluoroacetic acid, methylene chloride, and triisopropylsilane.

### Claim 13 (depends on 1)

The γ-AApeptide prepared by the process of claim 1, wherein the γ-AApeptide is a cyclic γ-AApeptide.

### Claim 14 (depends on 1)

The γ-AApeptide prepared by the process of claim 1, the process further comprising the step of purifying the γ-AApeptide by high performance liquid chromatography.

### Claim 15 (depends on 11)

The γ-AApeptide prepared by the process of claim 11, the process further comprising lyophizing the γ-AApeptide.

### Claim 16 (depends on 1)

The γ-AApeptide prepared by the process of claim 1, the process further comprising: lyophizing the γ-AApeptide.

### Claim 17 (depends on 1)

The γ-AApeptide prepared by the process of claim 1, wherein the substituted or unsubstituted alkanoic acid is ethanoic acid or 4-methyl pentanoic acid.

### Claim 18 (depends on 1)

The γ-AApeptide prepared by the process of claim 1, wherein the substituted or unsubstituted 5-membered heterocyclic ring is selected from furanyl, thienyl, pyrrolyl, N-alkyl pyrrolyl, or imidazole.

### Claim 19 (depends on 1)

The γ-AApeptide prepared by the process of claim 1, wherein the substituted or unsubstituted aryl is a substituted or unsubstituted hydrocinnamic acid.

### Claim 20 (depends on 19)

The γ-AApeptide prepared by the process of claim 19, wherein the substituted or unsubstituted hydrocinnamic acid is α-cyano-4-hydroxy-cinnamic acid.