# US 10,479,854 B2 · Conjugate for treating malaria

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- Number: US 10,479,854 B2
- Document ID: US10479854B2
- Status: Granted
- Kind: B2
- Application number: 15/503,175
- Filed: 2015-08-12
- Published: 2017-08-17
- Granted: 2019-11-19
- Earliest claimed: 2014-08-12
- Assignees: Stellenbosch University
- Applicants: Stellenbosch University
- Inventors: Lubertus Klumperman; Paul William Reader; Marina Rautenbach
- Web page: https://patentgrep.com/patent/US10479854B2

## CPC

- C08F 226/10: N-Vinyl-pyrrolidone
- A61K 38/08: Peptides having 5 to 11 amino acids {(A61K38/043 - A61K38/046 take precedence)}
- A61K 47/58: obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. poly[meth]acrylate, polyacrylamide, polystyrene, polyvinylpyrrolidone, polyvinylalcohol or polystyrene sulfonic acid resin
- A61K 47/6907: {the form being a microemulsion, nanoemulsion or micelle}
- A61P 33/06: Antimalarials
- C08F 2810/40: taking place solely at one end or both ends of the polymer backbone, i.e. not in the side or lateral chains
- 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
- C08F: MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
- 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

A peptide-polymer conjugate is provided for use in treating malaria infections, and in particular terminal or drug resistant malaria infections. The conjugate is formed from a polymer to which a peptide having activity against a malaria parasite is co-valently attached. The peptide is a cyclic decapeptide from the closely-related group of tyrocidines, tryptocidines, phenycidines and gramicidin S, and the polymer is a hydrophilic and biocompatible polymer with a terminal thiol, such as poly(N-vinylpyrrolidone) (PVP). The polymer chains can be decorated with a hydrophilic targeting ligand that specifically targets an epitope on red blood cells, and in particular red blood cells infected with a plasmodial parasite. A method for synthesising the peptide-polymer conjugate is also provided.

## Claims

### Claim 1

A peptide-polymer conjugate comprising a polymer to which an antiplasmodial peptide is covalently attached, wherein the antiplasmodial peptide is a cyclic decapeptide having an amino acid sequence of cyclo(X10-X1-Leu-D-Phe-Pro-X2-X3-X4-X5-X6) (SEQ ID NO: 1), where:
X10 is Val, Ile, or Leu;
X1 is Orn or Lys;
X2 is Val, Leu, Ile, Phe, Trp, or Tyr;
X3 is the D-isomer of Val, Leu, Ile, Phe, Trp, Tyr, or L-isomer of Orn or Lys;
X4 is Asn, Gln or Leu;
X5 is Gln or the D-isomer of Phe; and
X6 is Tyr, Phe, Trp, Pro, or hydroxyproline;
wherein the antiplasmodial peptide is conjugated to the polymer by way of a linkage comprising a beta-thiopropionate or beta-thiopropionamide, which causes the ester or amide linkage to be unstable and to release the antiplasmodial peptide at acidic pH, the linkage being formed by:
modifying the antiplasmodial peptide to comprise an acrylate ester or acrylamide, and
covalently linking the acrylate ester or acrylamide of the modified antiplasmodial peptide to a thiol end-group of a chain end of the polymer via Michael addition, and
wherein the peptide-polymer conjugate can be taken up by erythrocytes and has activity against a malaria parasite.

### Claim 2 (depends on 1)

The peptide-polymer conjugate according to claim 1, wherein the cyclic decapeptide is a tyrocidine with the sequence cyclo(X10-X1-Leu-D-Phe-Pro-X7-X8-Asn-Gln-X9) (SEQ ID NO: 2), where:
X10 is Val, Ile, or Leu;
X1 is Orn or Lys;
X7 is Trp or Phe;
X8 is D-Trp or D-Phe; and
X9 is Tyr, Trp, or Phe.

### Claim 3 (depends on 1)

The peptide-polymer conjugate according to claim 1, wherein the cyclic decapeptide is gramicidin S, with the amino acid sequence of cyclo(Val-X1-Leu-D-Phe-Pro-Val-X1-Leu-D-Phe-Pro) (SEQ ID NO: 3).

### Claim 4 (depends on 1)

The peptide-polymer conjugate according to claim 1, wherein the cyclic decapeptide has an amino acid sequence selected from any one of SEQ ID NOs: 6-177.

### Claim 5 (depends on 1)

The peptide-polymer conjugate according to claim 1, wherein the polymer is selected from the group consisting of poly(N-vinylpyrrolidone), poly(ethylene oxide), poly((ethylene oxide)-co-(propylene oxide)), poly(oligo(ethylene oxide)acrylate), poly(2-hydroxypropyl acrylamide), and poly(oligo(ethylene oxide)methacrylate).

### Claim 6 (depends on 1)

The peptide-polymer conjugate according to claim 1, wherein the antiplasmodial peptide is conjugated to the chain end of the polymer.

### Claim 7 (depends on 1)

The peptide-polymer conjugate according to claim 1, further comprising a hydrophilic targeting ligand selected from the group consisting of peptides having amino acid sequences of SEQ ID NOs: 178 185.

### Claim 8 (depends on 1)

A method of treating malaria, the method comprising administering a therapeutically effective amount of a peptide-polymer conjugate as claimed in claim 1 to a patient in need thereof.

### Claim 9 (depends on 8)

The method according to claim 8, wherein the therapeutically effective amount of the peptide-polymer conjugate comprises an amount of the peptide which is sub-therapeutic for treating malaria when the peptide is administered in an unconjugated form.