A non-hydrolysable peptidomimetic for mitochondrial targeting

-γ-amino-L-proline derivative. This peptidomimetic exhibited excellent membrane translocation efficiency, mitochondrial targeting ability, and biocompatibility. Mitochondrial targeting was confirmed to be dependent on the electrochemical potential generated by the electron transport chain. The presence of non-natural amino acids rendered the compound exceptionally stable in the presence of proteases, maintaining its integrity and functionality for targeting the organelle even after 1 week of incubation in serum. This stability, coupled with its targeting abilities and the low cytosolic/endosomal residual signal, facilitated the tracking of relevant mitochondrial dynamics, including fission events and intracellular movement. Additionally, this peptidomimetic scaffold allowed the sustained and precise mitochondrial targeting of a pH sensitive ratiometric probe, 5(6)-carboxy-SNARF-1, which enabled mitochondrial pH monitoring. In summary, our study introduces a biomimetic peptide with exceptional mitochondria-targeting properties, ensuring stability in biological media and offering insights into crucial mitochondrial processes.