Compounds and methods for modulating functions of nonclassical cadherins

A method for identifying a compound that modulates desmosomal cadherin-mediated cell adhesion, comprising:

• (a) determining a level of similarity between a three-dimensional structure of a candidate compound and a three-dimensional structure of a peptide comprising an amino acid sequence as set forth in SEQ ID NO:1 or SEQ ID NO:2 and a cell adhesion modulating activity;
• and
• (b) identifying an alteration in the structure of the candidate compound that results in a three-dimensional structure with an increased similarity to the three-dimensional structure of the peptide;
• and therefrom identifying a compound that has the ability to modulate desmosomal cadherin-mediated cell adhesion.

A cell adhesion modulating agent that

• (a) modulates atypical cadherin-mediated cell adhesion;
• and
• (b) comprises
• (i) a Trp-containing cell adhesion recognition sequence of an atypical cadherin molecule, but contains no more than 14 consecutive amino acid residues present within the atypical cadherin molecule;
• wherein the Trp-containing cell adhesion recognition sequence is
• A) the amino acid sequence Gly/Asp/Ser-Trp-Val/Ile/Met-Trp-Asn-Gln (SEQ ID NO:5), wherein Gly/Asp/Ser is an amino acid selected from the group consisting of Gly, Asp and Ser, and Val/Ile/Met is an amino acid selected from the group consisting of Val, Ile and Met, or
• B) the amino acid sequence Ala-Trp-Val-Ile-Pro-Pro (SEQ ID NO:6);
• (ii) a conservative analogue of SEQ ID NO:5 or SEQ ID NO:6;
• (iii) an antibody or antigen-binding fragment thereof that specifically binds to SEQ ID NO:5 or SEQ ID NO:6;
• or
• (iv) a peptidomimetic of SEQ ID NO:5 or SEQ ID NO:6.

A method for identifying a compound that modulates cell adhesion, comprising:

• (a) determining a level of similarity between a three-dimensional structure of a candidate compound and a three-dimensional structure of a peptide comprising an amino acid sequence as set forth in SEQ ID NO:
• 5 or SEQ ID NO:
• 6 and a cell adhesion modulating activity;
• and
• (b) identifying an alteration in the structure of the candidate compound that results in a three-dimensional structure with an increased similarity to the three-dimensional structure of the peptide;
• and therefrom identifying a compound that has the ability to modulate cell adhesion.

A method for evaluating a peptidomimetic for the ability to modulate cell adhesion, comprising:

• (a) culturing neurons on a monolayer of cells that express atypical cadherin in the presence and absence of a peptidomimetic, under conditions and for a time sufficient to allow neurite outgrowth, wherein the peptidomimetic has a three-dimensional structure that is substantially similar to a three-dimensional structure of a peptide having an amino acid sequence as set forth in SEQ ID NO:
• 5 or SEQ ID NO:
• 6 and a cell adhesion modulating activity;
• (b) determining a mean neurite length for said neurons;
• and
• (c) comparing the mean neurite length for neurons cultured in the presence of peptidomimetic to the neurite length for neurons cultured in the absence of the peptidomimetic, and therefrom determining whether the peptidomimetic modulates cell adhesion.

A method for evaluating a peptidomimetic for the ability to modulate cell adhesion, comprising:

• (a) culturing cells that express an atypical cadherin in the presence and absence of a peptidomimetic, under conditions and for a time sufficient to allow cell adhesion, wherein the peptidomimetic has a three-dimensional structure that is substantially similar to a three-dimensional structure of a peptide having an amino acid sequence as set forth in SEQ ID NO:
• 5 or SEQ ID NO:
• 6 and a cell adhesion modulating activity;
• and
• (b) visually evaluating the extent of cell adhesion among said cells, and therefrom identifying a peptidomimetic capable of modulating cell adhesion.

A method for evaluating a peptidomimetic for the ability to modulate atypical cadherin-mediated cell adhesion, comprising:

• (a) contacting an epithelial surface of skin with a test marker in the presence and absence of a peptidomimetic, wherein the peptidomimetic has a three-dimensional structure that is substantially similar to a three-dimensional structure of a peptide having an amino acid sequence as set forth in SEQ ID NO:
• 5 or SEQ ID NO:
• 6 and a cell adhesion modulating activity;
• and
• (b) comparing the amount of the test marker that passes through said skin in the presence of the peptidomimetic to the amount that passes through skin in the absence of the peptidomimetic, and therefrom determining whether the peptidomimetic modulates cell adhesion.

A method for evaluating the ability of a peptidomimetic to modulate atypical cadherin-mediated cell adhesion, comprising:

• (a) contacting a blood vessel with a peptidomimetic, wherein the peptidomimetic has a three-dimensional structure that is substantially similar to a three-dimensional structure of a peptide having an amino acid sequence as set forth in SEQ ID NO:
• 5 or SEQ ID NO:
• 6;
• and
• (b) comparing the extent of angiogenesis of the blood vessel to a predetermined extent of angiogenesis observed for a blood vessel in the absence of the peptidomimetic, and therefrom determining whether the peptidomimetic modulates cell adhesion.