Structure-forward targeting of claudins with synthetic binders

Claudins regulate molecular transport between cells via the paracellular route at tight junctions in epithelial and endothelial tissues and are prime targets for biologic therapies. Claudin-claudin interactions through their extracellular segments facilitate form and function of tight junction barriers, making for defined targetable surfaces. However, developing biologic or small molecule binders against claudin extracellular segments is challenging because they are small, dynamic, and no structures of assemblies exist to guide efforts to rationally design binders. Here, I review claudin targeting strategies, recent advances using natural and synthetic molecules, and the impact these molecules have had on claudin or tight junction biology. I surmise that the therapeutic promise of any molecule is dependent on deeply considering how claudins assemble and what structures they take within and outside of tight junctions. This review thus focuses on structure-forward themes, with the hope of providing a framework for researchers to apply this knowledge in the design and development of new claudin-binding molecules with diverse properties, mechanisms, and functions.