The central role of mitochondria in cellular energy production, reactive oxygen species generation and apoptotic cell death make them an attractive therapeutic target for a variety of diseases. Access to the interior of this organelle is, however, limited by the biophysical properties of its membranes. In order to overcome this restriction, our lab has developed mitochondria-penetrating peptides - composed of alternating cationic and hydrophobic amino acid residues - that act as organelle-specific delivery vectors. Here we present the design and characterization of a mitochondrial-targeted conjugate of a topoisomerase inhibitor. Mitochondrial sequestration of this inhibitor changes the cellular target from an essential topoisomerase located in the nucleus to another essential, homologous, mitochondrial variant. Repurposing this potential cancer therapeutic alters its toxicity in a panel of mammalian cell lines and leads to the generation of cellular stress originating from the mitochondrion.

Mitochondria-penetrating peptides as drug delivery vectors

245th National Meeting (2013)

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