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Publication Number
US-8785374-B2
Publication Date
2014-07-22
Expiration Date
Abstract
The present invention provides novel peptides that inhibit and/or reduce the opening of mammalian tight junctions, i.e. peptide tight junction antagonists. The present invention also provides methods for the treatment of excessive or undesirable permeability of a tissue by administering to a subject suffering from such a condition a composition comprising a peptide tight junction antagonist of the invention.
Core Innovation
The described invention relates to peptide tight junction antagonists that inhibit or reduce tight junction opening in a tissue containing tight junctions. The invention targets tight junction opening mediated by zonula occludens and related mechanisms, including Zonula occludens toxin (ZOT) and zonulin-mediated pathways as described in the document. The pharmaceutical approach is based on administering a peptide antagonist intended to reduce excessive barrier permeability.
The core treatment concept is a method of treating an excessive or undesirable permeability of a tissue containing tight junctions in a subject by administering a pharmaceutical composition comprising a peptide tight junction antagonist. In the independent claim, the peptide antagonist is defined by the formula X1-X2-X3-X4-X5, where X4 is selected from Pro and Ala and X5 is Gly, Gln, or Ala, with X3 being a natural or non-natural amino acid and X1 and X2 being optional natural or non-natural amino acids. The described peptide antagonist is used to address mammalian permeability associated with barrier dysfunction.
The document further describes pharmaceutical compositions and delivery approaches for administering the peptide tight junction antagonists, including intestinal delayed release and pulmonary delivery (solution aerosol and powder aerosol). The partial content also reports in vitro evaluation using CaCo-2 cells, including measurements of trans-epithelial electrical resistance (TEER) and permeability using Lucifer Yellow flux. The antagonists are reported to attenuate permeability changes induced by a ZOT-agonist (SEQ ID NO:70, FCIGRL), with results summarized in a classification table of antagonist sequences by inhibition outcomes.
Claims Coverage
The partial content provides one independent claim (clm-00001). This independent claim covers a method of treating excessive or undesirable tissue permeability at tight junctions using a pharmaceutical composition containing a specific five-amino-acid-pattern peptide tight junction antagonist, with residue-position constraints defining the peptide structure.
Five-amino-acid peptide antagonist for treating excessive permeability at tight junctions
Administering to the subject a pharmaceutical composition comprising a peptide tight junction antagonist having three to five amino acids, wherein the peptide is defined by the formula X1-X2-X3-X4-X5; X1 is optional, X2 is optional, X3 is a natural or non-natural amino acid, X4 is selected from Pro and Ala, and X5 is Gly, Gln, or Ala.
The claim scope is centered on therapeutic administration of a five-amino-acid-pattern peptide tight junction antagonist with fixed constraints at X4 (Pro or Ala) and X5 (Gly, Gln, or Ala), together with optional positioning at X1 and X2 and a natural or non-natural amino acid at X3.
Stated Advantages
Not explicitly described in patent.
Documented Applications
Not explicitly described in patent.
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