Mitochondria-penetrating Peptides: Characterization and Cargo Delivery

A class of mitochondria-penetrating peptides (MPPs) was studied in an effort to optimize their applications in the delivery of bioactive cargo to this therapeutically important organelle. The sequence requirements for mitochondrial entry were monitored, and it was discovered that while an alternating cationic/hydrophobic residue motif is not required, the inclusion of a stretch of adjacent cationic amino acids can impede access to the organelle. In addition, a variety of C-terminal cargos were tested to determine if there are limitations to the lipophilicity, charge, or polarity of compounds that can be transported to mitochondria by MPPs. Furthermore, these systematic studies aided the design and synthesis of a copper-binding MPP for the delivery of copper ions to mitochondria for the potential rescue of disorders associated with copper-deficiency. The results reported demonstrate that MPPs are versatile transporters that may have a wide range of biological applications.MAS