An essential step in preclinical drug development is confirming the specific binding of the novel therapeutic molecule to the protein target. Transmembrane proteins (TPs) such as ion channels, receptors, or transporters present a large group of targets involved in cancer and other diseases. Due to their complexity, producing those proteins in sufficient amounts is far more challenging than for their soluble counterparts, presenting a bottleneck in the drug discovery workflow.

Novel approaches to facilitate drug development include full-length transmembrane protein platforms, offering purified, high-quality TPs as off-the-shelf items for use in drug-target interaction analyses.

Meet the Claudin family: Gatekeepers in cancer

Examples of TP drug targets can be found in the Claudin protein family, a group of TPs playing a central role in the tight junctions – gatekeeping structures that regulate the flow of ions and water between epithelial and endothelial cells.

Among other functions, tight junctions support tissue structure integrity, preventing the migration of cancer cells through the endothelial barrier into the bloodstream. Recent studies have shown that abnormal expression rates of Claudin protein family members are related to tumor growth and metastasis, making them relevant therapeutic targets and cancer prognosis factors.

Claudins consist of four transmembrane-spanning domains with peptide loops located on the outside of the membrane. Together, those loops form three-dimensional structures or epitopes targeted by therapeutic or diagnostic antibodies.

“Producing only the isolated soluble loops of the Claudin proteins would be fast and easy. However, we know that because the individual peptides do not interact correctly, the three-dimensional structure required for reliable antibody screening does not form. But when we express Claudins as full-length TPs, the transmembrane domains hold the external loops in the correct position,” explained Dr. Spencer Chiang, Communication Manager at ACROBiosystems.

Interaction studies with therapeutic molecules and antibodies can only yield meaningful results when the target is presented in its biologically relevant conformation, calling for methods that enable the production of correctly folded, active, full-length TPs. Those methods, however, are still challenging to establish and vary between individual protein targets.

Click to read the full text: https://www.labiotech.eu/partner/drug-development-transmembrane-protein-platform/

This insight article is created by Labiotech.eu
Writer:Dr. Ute Boronowsky

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2. Newly Launched FLAG Claudin Family Proteins Facilitate Innovative Drug Development