Bridging membrane-active peptides: comparison of three different methods to rigidify the peptide backbone

Backbone rigidification is frequently used to enhance both function and stability of membrane-active peptides. However, while it does reduce the backbone flexibility, its impact depends heavily on the chosen method. In this study, we used a recently developed membrane-active peptide as candidate to evaluate ease of synthesis, impact on secondary structure, and biological activity of triazolyl- and m-xylene-bridging, and disulfide bond formation. Structural confinement was achieved solely through the triazolyl-bridge, yet the cells responded similarly to the m-xylene-bridged peptide. Our results highlight the complex relationship between the peptide, cellular membranes, and chemical derivatization.