Peptide inhibitors of tight junction permeability
Inventors
Alkan, Sefik • Tamiz, Amir • Kitchens, Kelly Marie • Durai, Malarvizhi • Poloso, Neil • Carrasco, Rosa A.
Assignees
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Publication Number
US-11149063-B2
Publication Date
2021-10-19
Expiration Date
Abstract
Novel compounds and methods for the inhibition of biological barrier permeability and for the inhibition of peptide translocation across biological barriers are identified. Assays for determining modulators of biological barrier permeability and for peptide translocation across biological barriers are provided. Methods for treating diseases relating to aberrant biological barrier permeability and peptide translocation across biological barriers are provided. Such diseases include celiac disease, necrotizing enterocolitis, diabetes, cancer, inflammatory bowel diseases, asthma, COPD, excessive or undesirable immune response, gluten sensitivity, gluten allergy, food allergy, rheumatoid arthritis, multiple sclerosis, immune-mediated or type 1 diabetes mellitus, systemic lupus erythematosus, psoriasis, scleroderma and autoimmune thyroid diseases.
Core Innovation
The invention concerns peptide inhibitors of tight junction permeability that block tight-junction opening and/or inhibit translocation of gluten-derived peptides across biological barriers. It links increased permeability to inflammatory and autoimmune diseases, including celiac disease and necrotizing enterocolitis. The peptide inhibitors are provided as part of a pharmaceutical composition designed to modulate biological barrier permeability.
The disclosed compositions include peptide inhibitors of the sequence Gly-Gly-(d)Val-(d)Leu-(d)Val-(d)Gln-(d)Pro-Gly (SEQ ID NO:93) and one or more enteric agents. The enteric agents are stable in gastric fluid but dissolve in intestinal fluid, supporting enteric-delayed release. The document further connects the permeability increase to immune-cell secreted factors, including PBMC and THP-1 based observations after stimulation with LPS or pepsin/trypsin-treated gliadin (PTG).
The document describes assessment concepts for tight junction permeability modulation using transepithelial electrical resistance (TEER) and Lucifer Yellow flux. It reports that specific peptides, including PYPQPQLPY (SEQ ID NO:163) and a panel of gliadin peptide permeability inhibitors (SEQ ID NOs:1-162), can prevent TEER reduction and/or reduce LY permeability. The enteric-delayed release formulation criteria include gastric stability and intestinal release behavior, enabling peptide release in targeted gastrointestinal conditions.
Claims Coverage
The independent claim defines a pharmaceutical composition with two core elements—an enteric-soluble tight-junction permeability peptide inhibitor (SEQ ID NO:93) and an enteric agent that is stable in gastric fluid but dissolves in intestinal fluid—amounting to inventive features that are further refined by dependent claims specifying where and how substantially the peptide is released and by method claims for inhibiting increased intestinal epithelial barrier permeability in patient disease contexts.
Enteric-soluble tight-junction permeability peptide inhibitor composition
A pharmaceutical composition comprising an effective amount of a peptide inhibitor of tight junction permeability of the sequence Gly-Gly-(d)Val-(d)Leu-(d)Val-(d)Gln-(d)Pro-Gly (SEQ ID NO:93), and one or more enteric agents.
Gastric-stable, intestinal-dissolving enteric agents
The one or more enteric agents are stable in gastric fluid but dissolve in intestinal fluid.
Duodenum or jejunum substantial release
The composition is configured to substantially release the peptide in the duodenum or the jejunum.
Gastric release constraint at pH 5 or less
The composition releases 30% or less of peptide in gastric fluid with a pH of 5 or less in approximately sixty minutes.
Intestinal release constraint at pH 5 or greater
The composition releases 70% or more of peptide in intestinal fluid with a pH of 5 or greater in approximately sixty minutes.
Inhibiting increased intestinal epithelial barrier permeability in a patient
A method for inhibiting increased intestinal epithelial barrier permeability in a patient by administering the composition to the patient’s epithelial barrier.
Necrotizing enterocolitis patient indication
The method is characterized by the patient having necrotizing enterocolitis.
Overall, the claim coverage centers on an enteric-delayed pharmaceutical composition combining the peptide inhibitor (SEQ ID NO:93) with gastric-stable/intestinal-dissolving enteric agents, optionally targeting duodenum/jejunum release, meeting defined gastric versus intestinal release thresholds, and using the composition to inhibit increased intestinal epithelial barrier permeability in patients, including those with necrotizing enterocolitis.
Stated Advantages
Blocks tight-junction (TJ) opening and/or inhibits translocation of gluten-derived peptides across biological barriers.
Prevents TEER reduction and/or reduces Lucifer Yellow (LY) permeability.
Inhibits increased intestinal epithelial barrier permeability in a patient.
Documented Applications
Treatment methods directed to inhibiting increased intestinal epithelial barrier permeability in a patient, including methods where the patient has necrotizing enterocolitis.
Disease contexts associated with increased permeability referenced in the document include celiac disease and necrotizing enterocolitis, as well as inflammatory/autoimmune conditions listed in the document summary (e.g., inflammatory bowel disease, type 1 diabetes, autoimmune hepatitis, multiple sclerosis, rheumatoid arthritis, systemic lupus erythematosus, psoriasis, scleroderma, asthma/COPD, food allergy, and immune response disorders).
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