This invention is in the field of medicinal pharmacology. In particular, the invention relates to protease activated receptor type 2 (PAR2) modulating compounds (e.g., mimetic peptides), compositions comprising such modulating compounds, and their use as therapeutics for the treatment of conditions involving PAR2 activity.

This invention is in the field of medicinal pharmacology. In particular, the invention relates to protease activated receptor type 2 (PAR2) modulating compounds (e.g., mimetic peptides), compositions comprising such modulating compounds, and their use as therapeutics for the treatment of conditions involving PAR2 activity.

Disclosed is a general, reversible bicyclization strategy to increase both the proteolytic stability and cell permeability of peptidyl drugs. A peptide drug is fused with a short cell-penetrating motif and converted into a conformationally constrained bicyclic structure through the formation of a pair of disulfide bonds. The resulting bicyclic peptide has greatly enhanced proteolytic stability as well as cell-permeability. Once inside the cell, the disulfide bonds are reduced to produce a linear, biologically active peptide. This strategy was applied to generate a cell-permeable bicyclic peptidyl inhibitor against the NEMO-IKK interaction.

Disclosed is a general, reversible bicyclization strategy to increase both the proteolytic stability and cell permeability of peptidyl drugs. A peptide drug is fused with a short cell-penetrating motif and converted into a conformationally constrained bicyclic structure through the formation of a pair of disulfide bonds. The resulting bicyclic peptide has greatly enhanced proteolytic stability as well as cell-permeability. Once inside the cell, the disulfide bonds are reduced to produce a linear, biologically active peptide. This strategy was applied to generate a cell-permeable bicyclic peptidyl inhibitor against the NEMO-IKK interaction.

A compound represented by formula (1):

##STR00001##

wherein b represents an integer of 1 to 5; X represents —NH— or —CO—; Z represents a group represented, for example, by formula (Z-1); R.sup.1 represents a hydrogen atom or (AB).sub.m; AB represents a particular amino acid residue, and when there is a plurality of ABs, each AB may be the same as or different from each other and ABs are bonded to each other via an amide bond; m represents an integer of 1 to 9; R.sup.2 represents a hydroxy group or (AC).sub.g; AC represents a particular amino acid residue, and when there is a plurality of ACs, each AC may be the same as or different from each other and ACs are bonded to each other via an amide bond; and g represents an integer of 1 to 9,
or a salt thereof.

A compound represented by formula (1):

##STR00001##

wherein b represents an integer of 1 to 5; X represents —NH— or —CO—; Z represents a group represented, for example, by formula (Z-1); R.sup.1 represents a hydrogen atom or (AB).sub.m; AB represents a particular amino acid residue, and when there is a plurality of ABs, each AB may be the same as or different from each other and ABs are bonded to each other via an amide bond; m represents an integer of 1 to 9; R.sup.2 represents a hydroxy group or (AC).sub.g; AC represents a particular amino acid residue, and when there is a plurality of ACs, each AC may be the same as or different from each other and ACs are bonded to each other via an amide bond; and g represents an integer of 1 to 9,
or a salt thereof.

The invention relates to macrocyclic peptides and pharmaceutical compositions thereof. The invention further relates to pharmaceutical compositions for modulating opioid receptor activity.

Methods for enhancing the immune response and/or treatment of diseases such as cancer comprising an agent that specifically binds TIGIT are disclosed. The TIGIT-binding agents may include polypeptides, antibodies, and/or bispecific agents.

Methods for enhancing the immune response and/or treatment of diseases such as cancer comprising an agent that specifically binds TIGIT are disclosed. The TIGIT-binding agents may include polypeptides, antibodies, and/or bispecific agents.

Peptides and methods of use thereof, are disclosed for use in treating various diseases and disorders, including inflammation, pain, oral mucositis, oral lesions, and cancer. The peptides modulate the activity of the transcription factor NF κB.