BETA-PEPTIDES WITH ANTIFUNGAL ACTIVITY

• US 20080166388A1
• Filed: 09/04/2007
• Published: 07/10/2008
• Est. Priority Date: 09/01/2006
• Status: Active Grant

• Current Assignee: Wisconsin Alumni Research Foundation (University of Wisconsin System)
• Original Assignee: Wisconsin Alumni Research Foundation (University of Wisconsin System)
• Inventors: Palecek, Sean P., Gellman, Samuel H., Pomerantz, William C.
• Granted Patent: US 9,168,329 B2
• Time in Patent Office: Days
• US Class Current: 424/423
• CPC Class Codes: 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
• CPC Class Codes: A61L 2300/252 Polypeptides, proteins, e.g. glycoproteins, lipoproteins, cytokines
• CPC Class Codes: A61L 27/54 Biologically active materials, e.g. therapeutic substances A61L27/227 takes precedence
• CPC Class Codes: A61L 29/16 Biologically active materials, e.g. therapeutic substances A61L29/048 takes precedence
• CPC Class Codes: A61L 31/16 Biologically active materials, e.g. therapeutic substances A61L31/047 takes precedence
• CPC Class Codes: A61P 31/10 Antimycotics
• CPC Class Codes: C07K 5/0202 containing the structure -NH-X-X-C(=0)-, X being an optionally substituted carbon atom or a heteroatom, e.g. beta-amino acids

Abstract

The present invention is directed to the design, synthesis and use of various β-peptides exhibiting antifungal activity. The β-peptides are relatively short in length, adopt globally amphiphilic conformations, and cause little lysis of human red blood cells at concentrations that kill Candida albicans, a common human fungal pathogen.

Claims

1. A method of inhibiting fungal growth, comprising contacting a fungus to be inhibited with an inhibitory amount of a β

-peptide.

2. The method according to claim 1, wherein the β

-peptide has the structure;

(R¹—

R²—

R³)₃

wherein R¹, R², and R³ of each triad are independently selected from β

-amino acid residues bearing hydrophobic and cationic side chains such that the R¹—

R²—

R³ triads in the β

-peptide consist of β

-amino acid residues bearing hydrophobic and cationic side chains in the sequential pattern hydrophobic-hydrophobic-cationic, hydrophobic-cationic-hydrophobic, or cationic-hydrophobic-hydrophobic.

3. The method according to claim 2 wherein said β

-amino acid residues are homo-chiral.

4. The method according to claim 3 wherein R¹ is ACHC, R² is ACHC, β

³Val, β

³Leu, or β

³Phe; and

R³ is β

³Lys or β

³Arg.

5. The method according to claim 4 wherein said β

-peptide further includes a β

³Tyr residue at its N-terminus.

6. The method according to claim 2 wherein said β

-peptide further includes at least one terminus capping group.

7. The method according to claim 2 wherein the β

-peptide is selected from the group consisting of (ACHC-β

³Val-β

³Lys)₃, β

³Tyr-(ACHC-β

³Val-β

³Lys)₃, β

³Tyr-(ACHC-β

³Leu-β

³Lys)₃, β

³Tyr-(ACHC-β

³Phe-β

³Lys)₃, β

³Tyr-(β

³Val-β

³Val-β

³Lys)₃, β

³Tyr-(ACHC-ACHC-β

³Lys)₃, (ACHC-β

³Val-β

³Lys)₃, β

³Tyr-(ACHC-β

³Val-β

³Arg)₃, β

³Tyr-(β

³Leu-ACHC-β

³Lys)₃ and C9-β

³Tyr-(ACHC-ACHC-β

³Lys)₃.

8. An antifungal composition, comprising:

(a) an inhibitory amount of a β

-peptide having the structure;

(R¹—

R²—

R³)₃

wherein R¹, R², and R³ of each triad are independently selected from β

-amino acid residues bearing hydrophobic and cationic side chains such that the R¹—

R²—

R³ triads in the β

-peptide consist of β

-amino acid residues bearing hydrophobic and cationic side chains in the sequential pattern hydrophobic-hydrophobic-cationic, hydrophobic-cationic-hydrophobic, or cationic-hydrophobic-hydrophobic; and

(b) a pharmaceutically-acceptable carrier.

9. The antifungal composition according to claim 8 wherein said β

-amino acid residues are homo-chiral.

10. The antifungal composition according to claim 9 wherein R¹ is ACHC, R² is ACHC, β

³Val, β

³Leu, or β

³Phe; and

R³ is β

³Lys or β

³Arg.

11. The antifungal composition according to claim 10 wherein said β

-peptide further includes a β

³Tyr residue at its N-terminus.

12. The antifungal composition according to claim 11 wherein said β

-peptide further includes an acyl group coupled to said β

³Tyr residue.

13. The antifungal composition according to claim 8 wherein said β

-peptide further includes at least one terminus capping group.

14. The antifungal composition according to claim 8 wherein the β

-peptide is selected from the group consisting of (ACHC-β

³Val-β

³Lys)₃, β

³Tyr-(ACHC-β

³Val-β

³Lys)₃, β

³Tyr-(ACHC-β

³Leu-β

³Lys)₃, β

³Tyr-(ACHC-β

³Phe-β

³Lys)₃, β

³Tyr-(3Val-β

³Val-β

³Lys)₃, β

³Tyr-(ACHC-ACHC-β

³Lys)₃, (ACHC-β

³Val-β

³Lys)₃, β

³Tyr-(ACHC-β

³Val-β

³Arg)₃, β

³Tyr-(3Leu-ACHC-β

³Lys)₃ and C9-β

³Tyr-(ACHC-ACHC-β

³Lys)₃.

22. A fungal resistant medical article comprising an article selected from a stent, valve, pacemaker, defibrillator, artificial joint, prosthesis, neurostimulator, ventricular assist device, congestive heart failure device, indwelling catheter, insulin pump, incontinence device, cochlear device, or embolic filter, said article at least partially coated with an antifungal composition according to claim 8.

23. A kit comprising a pharmaceutical composition according to claim 8 and a delivery device.

15. A method of treating fungal growth in a subject, comprising administering to the subject a therapeutically effective amount of a β

-peptide selected from the group consisting of (ACHC-β

³Val-β

³Lys)₃, β

³Tyr-(ACHC-β

³Val-β

³Lys)₃, β

³Tyr-(ACHC-β

³Leu-β

³Lys)₃, β

³Tyr-(ACHC-β

³Phe-β

³Lys)₃, β

³Tyr-(β

³Val-β

³Val-β

³Lys)₃, β

³Tyr-(ACHC-ACHC-β

³Lys)₃, (ACHC-β

³Val-β

³Lys)₃, β

³Tyr-(ACHC-β

³Val-β

³ Arg)₃, β

³Tyr-(β

³Leu-ACHC-β

³Lys)₃ and C9-β

³Tyr-(ACHC-ACHC-β

³Lys)₃.

16. A β

-peptide having the structure;

(ACHC—

R²—

R³)₃

wherein R² is β

³Val, β

³Leu or β

³Phe; and

R³ is β

³Lys or β

³Arg.

17. The β

-peptide according to claim 16 wherein said β

-peptide further includes a β

³Tyr residue at its N-terminus.

18. The β

-peptide according to claim 17 wherein said β

-peptide further includes an acyl group coupled to said β

³Tyr residue.

19. The β

-peptide according to claim 16 wherein said ACHC residues are in the S,S enantiomeric conformation.

20. The β

-peptide according to claim 21 wherein said ACHC, R² and R³ residues are homo-chiral.

21. The β

-peptide according to claim 16 wherein said β

-peptide further includes at least one terminus capping group.