MUC1 decoy peptides for treatment and prevention of bacterial infections

Patent metadata

Field	Value
Publication number	US-10537609-B2
Application number	US-201715630165-A
Country	US
Kind code	B2
Filing date	Jun 22, 2017
Priority date	Dec 23, 2014
Publication date	Jan 21, 2020
Grant date	Jan 21, 2020

Abstract

Pseudomonas aeruginosa flagellin protein recruits the mammalian host sialidase enzyme neuraminidase-1 (NEU1) to remove sialic acid residues from the extracellular domain of the mammalian cell-surface protein MUC1 (MUC1-ED), thereby exposing a cryptic binding site on the MUC1-ED protein backbone for flagellin binding. NEU1-driven MUC1-ED desialylation rapidly increases P. aeruginosa adhesion to the airway epithelium. MUC1-ED desialylation also increases MUC1-ED cleavage and shedding from the cell surface, where desialylated, shed MUC1-ED competitively blocks P. aeruginosa adhesion to cell-associated MUC1-ED. Presented herein are data showing that exogenously-administered, deglycosylated MUC1-ED peptides reduced adhesion of P. aeruginosa to airway epithelial cells. Also presented are data showing that administration of P. aeruginosa to mice in combination with deglycosylated MUC1-ED decreased P. aeruginosa recovered from the lungs at 48 hr and 72 hr post-infection. Such findings are extended to the methods of treatment and prevention of bacterial infections defined herein.

First claim

What is claimed is:

1. A method of treating or preventing a pulmonary infection caused by Pseudomonas aeruginosa in a subject, comprising administering to the subject a therapeutically effective amount of an ectodomain MUC1 decoy peptide comprising the amino acid sequence set forth in SEQ ID NO:3.

2. The method of claim 1 , wherein the pulmonary infection is treated.

3. The method of claim 1 , wherein the pulmonary infection is an infection of the lungs of a subject with cystic fibrosis or a ventilator-associated pneumonia.

4. The method of claim 1 , wherein the ectodomain MUC1 decoy peptide is formulated in a pharmaceutical formulation comprising the peptide and a pharmaceutically acceptable carrier or diluent.

5. The method of claim 1 further comprising administering a therapeutically effective amount of one or more antibiotics to the subject.

6. The method of claim 5 , wherein the one or more antibiotics are formulated in a pharmaceutical formulation comprising the antibiotic and a pharmaceutically acceptable carrier or diluent.

7. The method of claim 5 wherein the ectodomain MUC1 decoy peptide comprises the amino acid sequence set forth in SEQ ID NO:3 the antibiotic is cefepime.

8. The method of claim 5 wherein the ectodomain MUC1 decoy peptide and the one or more antibiotics are administered to the subject via separate administrations.

9. The method of claim 1 , wherein the administering comprises administering by inhalation.

Assignees

• Univ Maryland
• Us Veterans Affairs

Inventors

• Lillehoj Erik P
• Verceles Avelino C
• Goldblum Simeon E

Classifications

• A61P31/04

  Antibacterial agents · 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

• G01N2333/245

  Escherichia (G) · CPC title

• C07K14/4727

  Mucins, e.g. human intestinal mucin · CPC title

• G01N33/56911

  Bacteria · CPC title