Tension Promoted Sulfur Exchange for Cellular Delivery

Cellular delivery is crucial for the discovery and development of novel drugs and probes. However, the efficient and reliable delivery of bioactive molecules into cells remains both challenging and limited in scope. Therefore, there is an emerging interest to develop conceptually innovative approaches to precisely deliver relevant biomolecules to a target site. With this in mind, Matile and co-workers have taken a significant step forward by using epidithiodiketopiperazines (ETPs) for the nontoxic delivery of model probes to the cytosol and particularly the nucleus, without endosomal capture, making this approach “unstoppable” by all conventional inhibitors of endocytosis. In their previous studies, Matile and co-workers reported on the use of disulfide ring tension for thiol-mediated cellular uptake (Figure 1). These studies indicated that strained disulfides with decreasing CSSC dihedral angles (θ) react best with exofacial thiolates for covalent binding to the cell surface, thus increasing the uptake efficiencies. In the current work, ETPs are introduced to drive ring tension to the maximum (θ ≈ 0°) (Figure 1), which facilitates the delivery into cells through a novel multitarget hopping mode of action.