title: Peptide-Mediated Delivery of Chemical Probes and Therapeutics to Mitochondria.
abstract: Mitochondria are organelles with critical roles in key processes within eukaryotic cells, and their dysfunction is linked with numerous diseases including neurodegenerative disorders and cancer. Pharmacological manipulation of mitochondrial function is therefore important both for basic science research and eventually, clinical medicine. However, in comparison to other organelles, mitochondria are difficult to access due to their hydrophobic and dense double membrane system as well as their negative membrane potential. To tackle the challenge of targeting these important subcellular compartments, significant effort has been put forward to develop mitochondria-targeted systems capable of transporting bioactive cargo into the mitochondrial interior. Systems now exist that utilize small molecule, peptide, liposome, and nanoparticle-based transport. The vectors available vary in size and structure and can facilitate transport of a variety of compounds for mitochondrial delivery. Notably, peptide-based delivery scaffolds offer attractive features such as ease of synthesis, tunability, biocompatibility, and high uptake both in cellulo and in vivo. Owing to their simple and modular synthesis, these peptides are highly adaptable for delivering chemically diverse cargo. Key design features of mitochondria-targeted peptides include cationic charge, which allows them to harness the negative membrane potential of mitochondria, and lipophilicity, which permits favorable interaction with hydrophobic membranes of mitochondria. These peptides have been covalently tethered to target therapeutic agents, including anticancer drugs, to enhance their drug properties, and to provide probes for mitochondrial biology. Interestingly, mitochondria-targeted DNA damaging agents demonstrate high potency and the ability to evade resistance mechanisms and off-target effects. Moreover, a combination of mitochondria-targeted DNA damaging agents was applied to an siRNA screen for the elucidation of poorly understood mitochondrial DNA repair and replication pathways. In this work, a variety of novel proteins were identified that are essential for the maintenance of mitochondrial nucleic acids. Mitochondria-targeted peptides have also been used to increase the therapeutic window of antibacterial drugs with significant mammalian toxicity. Given the evolutionary similarity of mitochondria and bacteria, peptides are effective transporters that can target both of these entities. These antimicrobial peptides are highly effective even in difficult to target intracellular bacteria which reside within host cells. This peptide-based approach to targeting mitochondria has provided a variety of insights into the "druggability" of mitochondria and new biological processes that could be future drug targets. Nevertheless, the mitochondrial-targeting field is quite nascent and many exciting applications of organelle-specific conjugates remain to be explored. In this Account, we highlight the development and optimization of the mitochondria-penetrating peptides that our laboratory has developed, the unique applications of mitochondria-targeted bioactive cargo, and offer a perspective on important directions for the field.
authors.affiliation: Department of Chemistry, Faculty of Arts and Science, University of Toronto , Toronto, Ontario M5S 3H6, Canada.
authors.forename: Sae Rin
authors.initials: SR
authors.lastname: Jean
authors.affiliation: Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto , Toronto, Ontario M5S 3M2, Canada.
authors.forename: Marya
authors.initials: M
authors.lastname: Ahmed
authors.affiliation: Department of Biochemistry, Faculty of Medicine, University of Toronto , Toronto, Ontario M5S 1A8, Canada.
authors.forename: Eric K
authors.initials: EK
authors.lastname: Lei
authors.affiliation: Department of Biochemistry, Faculty of Medicine, University of Toronto , Toronto, Ontario M5S 1A8, Canada.
authors.forename: Simon P
authors.initials: SP
authors.lastname: Wisnovsky
authors.affiliation: Department of Chemistry, Faculty of Arts and Science, University of Toronto , Toronto, Ontario M5S 3H6, Canada.|Department of Biochemistry, Faculty of Medicine, University of Toronto , Toronto, Ontario M5S 1A8, Canada.|Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto , Toronto, Ontario M5S 3M2, Canada.
authors.forename: Shana O
authors.initials: SO
authors.lastname: Kelley
mesh_terms: D000900:Anti-Bacterial Agents / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology; D004247:DNA / Q000737:chemistry; D004249:DNA Damage; D004337:Drug Carriers / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D008928:Mitochondria / Q000378:metabolism*; D051336:Mitochondrial Membranes / Q000378:metabolism; D010455:Peptides / Q000737:chemistry / Q000378:metabolism*
chemical_list: D000900:Anti-Bacterial Agents; D000970:Antineoplastic Agents; D004337:Drug Carriers; D010455:Peptides; D004247:DNA