Theta defensin analogs

Patent metadata

Field	Value
Publication number	US-11021518-B2
Application number	US-202016914038-A
Country	US
Kind code	B2
Filing date	Jun 26, 2020
Priority date	Jun 26, 2019
Publication date	Jun 1, 2021
Grant date	Jun 1, 2021

Abstract

Novel peptide analogs of a θ-defensin have been developed that provide a biphasic effect in treating infection and/or sepsis. These analogs are active at concentrations below those needed to provide a bactericidal or bacteriostatic effect, and function by initially recruiting effector cells of the immune system to address the infective organism followed by regulation of the immune system to down regulate the inflammatory response characteristic of sepsis and septic shock. These novel θ-defensin analogs are protective at concentrations where naturally occurring θ-defensins have no apparent effect, and include a core set of structural and sequence features not found in native θ-defensin.

First claim

What is claimed is:

1. A cyclic peptide consisting of 14 amino acids and having the following structure:

wherein AA1 is glycine, AA3 and AA12 are cysteines joined by a disulfide bond, AA5 and AA10 are cysteines joined by a disulfide bond, AA4 is a first hydrophobic amino acid, AA11 is a second hydrophobic acid, AA6 is arginine, AA7 is arginine, AA8 is arginine, and wherein the cyclic peptide has two glycines and has four arginine residues that provide a positively charged content of about 28% at physiological pH, and wherein AA2, AA9, AA13, and AA14 are amino acids.

2. The cyclic peptide of claim 1 , wherein the first hydrophobic amino acid and the second hydrophobic amino acid are leucine or isoleucine.

3. The cyclic peptide of claim 1 , wherein AA2 is a third hydrophobic amino acid.

4. The cyclic peptide of claim 1 , wherein AA9 is a fourth hydrophobic amino acid.

5. The cyclic peptide of claim 1 , wherein AA13 is glycine.

6. The cyclic peptide of claim 1 , wherein AA14 is arginine.

7. The cyclic peptide of claim 1 , wherein at least one of AA4 and AA11 is not alanine or serine.

8. The cyclic peptide of claim 1 , wherein the cyclic peptide is MTD12813 (SEQ ID NO. 2).

9. A method of treating septic shock, comprising administering a cyclic peptide of claim 1 an animal at risk of septic shock.

10. The method of claim 9 , wherein the cyclic peptide is an analog of a θ-defensin, and wherein the cyclic peptide provides improved survival when applied systemically in a murine sepsis model relative to the θ-defensin.

11. The method of claim 9 , wherein the method provides a biphasic response on application to a murine model of sepsis, wherein the biphasic response comprises a first phase of recruitment of host effector cells having antimicrobial activity and a second phase of moderation of host inflammatory response.

12. The method of claim 9 , wherein the method inhibits TACE activity.

13. The method of claim 9 , wherein the method suppresses at least one of expression, processing, and release of a proinflammatory cytokine.

14. The method of claim 9 , wherein the cyclic peptide retains activity following exposure to environmental extremes of temperature, low pH, freezing and/or thawing, and dissolution in a biological matrix.

15. The method of claim 9 , wherein the cyclic peptide is non-immunogenic at doses effective to treat septic shock.

16. The method of claim 9 , wherein the cyclic peptide activates a host immune system to enhance host clearance of pathogens.

Assignees

• Selsted Michael E
• Tran Dat Q
• Schaal Justin B
• Univ Southern California

Inventors

• Selsted Michael E
• Tran Dat Q
• Schaal Justin B

Classifications

• C07K7/64 Primary

  Cyclic peptides containing only normal peptide links · CPC title

• C07K7/08 Primary

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

• A61P31/10

  Antimycotics · CPC title

• A61K38/00 Primary

  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

• A61P31/00 Primary

  Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics · CPC title