Compounds and methods for modulating desmosomal cadherin-mediated functions

Abstract

Modulating agents for inhibiting or enhancing desmosomal cadherin mediated cell adhesion are provided. The modulating agents comprise one or more of: (a) a peptide sequence that is at least 50% identical to a desmosomal cadherin CAR sequence; (b) a non-peptide mimetic of a desmosomal cadherin CAR sequence; (c) a substance, such as an antibody or antigen-binding fragment thereof, that specifically binds a desmosomal cadherin CAR sequence; and/or (d) a polynucleotide encoding a polypeptide that comprises a desmosomal cadherin CAR sequence or analogue thereof. Methods for using such modulating agents for modulating desmosomal cadherin-mediated cell adhesion in a variety of contexts are also provided.

Description

[0001] This application is a continuation of U.S. patent application Ser. No. 09 / 535,852, filed Mar. 27, 2000, now allowed; which is a continuation-in-part of U.S. patent application Ser. No. 09 / 187,859, filed Nov. 6, 1998, and issued as U.S. Pat. No. 6,358,920; which is a continuation-in-part of U.S. patent application Ser. No. 09 / 073,040, filed May 5, 1998, and issued as U.S. Pat. No. 6,472,367, all of which applications are incorporated by reference herein in their entireties.STATEMENT REGARDING SEQUENCE LISTING SUBMITTED ON CD-ROM[0002] The Sequence Listing associated with this application is provided on CD-ROM in lieu of a paper copy, and is hereby incorporated by reference into the specification. Three CD-ROMs are provided, containing identical copies of the sequence listing: CD-ROM No. 1 is labeled COPY 1, contains the file 407c10.app.txt which is 0.51 MB and created on Sep. 3, 2003; CD-ROM No. 2 is labeled COPY 2, contains the file 407c10.app.txt which is 0.51 MB and created...

AI Technical Summary

Problems solved by technology

Notwithstanding these recent advances, nonclassical cadherin function remains poorly understood at the biological and molecular levels.

Such modulating agents and compositions may inhibit or enhance cell adhesion.

The repeated contact with base makes the Merrifield resin unsuitable for Fmoc chemistry, and p-alkoxybenzyl esters linked to the resin are generally used.

The slow reactivity of azides and the formation of isocyanates by their disproportionation restrict the usefulness of this method.

In general, a modulating agent is an inhibitor of cell adhesion if contact of the test cells with the modulating agent results in a discernible disruption of cell adhesion.

Within certain cell adhesion assays, the addition of a modulating agent to cells that express a desmosomal cadherin results in disruption of cell adhesion.

For example, it is often particularly difficult to administer parenteral drugs to newborns and infants because of the difficulty associated with finding veins of acceptable caliber to catheterize.

Further, there are many clinical situations where it is difficult to maintain compliance.

Patients with diseases that are without symptoms, like patients with hypertension, are especially at risk of forgetting to take their medication as prescribed.

Similarly, administration of matrix-linked modulating agents may facilitate cell adhesion in skin grafting and prosthetic implants, and may prolong the duration and usefulness of collagen injection.

In consequence, adhesion of skin cells begins to fail, resulting in various kinds of blistering.

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