Peptide inhibitors of phosphoglycerate mutase and methods of use

Patent metadata

Field	Value
Publication number	US-10808010-B2
Application number	US-201716324424-A
Country	US
Kind code	B2
Filing date	Aug 10, 2017
Priority date	Aug 11, 2016
Publication date	Oct 20, 2020
Grant date	Oct 20, 2020

Abstract

Disclosed herein are isolated peptides inhibit activity of a cofactor-independent phosphoglycerate mutase. In some examples, the isolated peptide is 6-20 amino acids long and includes the amino acid sequence of any one of SEQ ID NOs: 1-22 or 54, an analog or derivative thereof, or a pharmaceutically acceptable salt or ester thereof. In some examples, the peptide is a cyclic peptide with an N-terminal ring of 6-15 amino acids (for example, 6-10 amino acids) and a C-terminal linear portion of 1-9 amino acids (for example, 3-8 amino acids. Also disclosed h are methods of treating or inhibiting an infection in a subject, including administering to the subject an effective amount of a composition including one of more of the disclosed peptides, or analogs or derivative thereof, or pharmaceutically acceptable salts or esters thereof.

First claim

We claim:

1. An isolated cyclic peptide comprising the amino acid sequence of any one of SEQ ID NOs: 1-6, 10-20, or 55-69 wherein the peptide includes an N-terminal ring structure of 7-13 amino acids and a C-terminal linear portion of 1-7 amino acids, wherein the N-terminal ring structure comprises a thioether linkage, or a pharmaceutically acceptable salt or ester thereof.

2. The isolated cyclic peptide of claim 1 , wherein the peptide comprises:

3. The isolated cyclic peptide of claim 1 , wherein at least one amino acid is a D-amino acid.

4. The isolated cyclic peptide of claim 3 , wherein the N-terminal amino acid is a D-amino acid.

5. The isolated cyclic peptide of claim 1 , wherein the thioether linkage is between an N-terminal acetyl group and a cysteine residue.

6. The isolated cyclic peptide of claim 1 , wherein the peptide comprises a C-terminal amide.

7. The isolated cyclic peptide of claim 1 , wherein the peptide comprises at least one N-methyl amide in the linear portion of the peptide.

8. The isolated peptide of claim 1 , wherein the peptide inhibits activity of cofactor-independent phosphoglycerate mutase with an IC 50 of 100 μM or less.

9. The isolated peptide of claim 8 , wherein the peptide inhibits activity of cofactor-independent phosphoglycerate mutase with an IC 50 of 1 pM to 100 μM.

10. A pharmaceutical composition comprising the isolated peptide of claim 1 and a pharmaceutically acceptable carrier.

11. A method of treating or inhibiting infection with an organism expressing at least one cofactor-independent phosphoglycerate mutase in a subject, comprising administering to the subject an effective amount of the pharmaceutical composition of claim 10 .

12. A method of treating or inhibiting infection with an organism expressing at least one cofactor-independent phosphoglycerate mutase in a subject, comprising administering to the subject an effective amount of the isolated peptide of claim 1 .

13. The method of claim 12 , wherein the subject is infected with an organism selected from the group consisting of a nematode, a trypanosome, a helminth, and a protozoan parasite.

14. The method of claim 13 , wherein the subject is infected with a nematode, and the nematode comprises one or more of Brugia malayi, Brugia timori, Wuchereria bancrofti, Onchocerca volvulus, Loa loa, Mansonella streptocerca, Mansonella perstans, Mansonella ozzardi, Dirofilaria immitis, Trichinella, Parafilaria bovicola, Onchocerca dermatan, Onchocerca ochengi, Onchocerca dukei, Stenofilaria assamensis , and Parafilaria multipapillosa.

15. The method of claim 12 , wherein the peptide is administered orally, intravenously, or topically.

16. The method of claim 12 , further comprising administering one or more of an antiparasitic or antibiotic agent to the subject.

Assignees

• Us Health
• Univ Tokyo
• New England Biolabs Inc

Inventors

• Inglese James
• Dranchak Patricia
• Macarthur Ryan
• Suga Hiroaki
• Yu Hao
• Carlow Clotilde
• Li Zhiru

Classifications

• C07K7/64 Primary

  Cyclic peptides containing only normal peptide links · CPC title

• C07K14/00

  Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof · CPC title

• C07K7/06

  having 5 to 11 amino acids · CPC title

• A61K38/00

  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 title

• C07K7/08

  having 12 to 20 amino acids (gastrins C07K14/595; somatostatins C07K14/655; melanotropins C07K14/68) · CPC title