Cell-penetrating peptide targeting mitochondria: Design, synthesis, characterization, and biological effects
2015 (English)Licentiate thesis, comprehensive summary (Other academic)
More than twenty years after the discovery of the first cell-penetrating peptide (CPP), a large number of both naturally occurring as well as engineered CPPs have been discovered. Generally, CPPs are short polycationic sequences of less than 30 amino acids that are able to translocate different cargoes into cells. They are amphipathic and net positively charged at physiological pH. The cargo can be covalently attached to the CPP, which can be achieved by expression as a fusion construct or by chemical coupling; or the cargo and carrier could bind each other non-covalently mainly through ionic interactions.
A series of CPPs targeting mitochondria (mtCPPs) were studied in an effort to optimize their applications for the reduction of reactive oxygen species targeting this therapeutically important organelle. Mitochondria have evolved to play a vital role in both life and death of eukaryotic cells, through involvement in numerous cellular functions, such as the proficient production of energy from ATP biosynthesis and the regulation of programmed cell death. As a result, dysfunction in the biochemical processes housed within this organelle is implicated in diverse diseases, including cancer, diabetes, and neurodegenerative disorders. Advancing mitochondrial medicine by probing the subcellular biochemistry or targeting therapeutics into this organelle has motivated the development of effective mitochondrial delivery vectors. A fluorescent probe was covalently attached at the N-terminus of the analog peptides to determine the cellular internalization and the possibility to be transported to mitochondria by mtCPPs. The results report the development of a novel cationic peptides (mtCPP-1), which is readily cell permeable and preferentially localize into the mitochondria of living mammalian cells. By substitutions with both natural and synthetic amino acids, and monitoring the intracellular localization by fluorescence microscopy, the mitochondrial accumulation with a cationic peptide was achieved. The biological and chemical characterization of mtCPP-1 revealed the importance of balancing the opposing characteristics of positive charge and lipophilicity to attain preferential sequestration into mitochondria, as well as provide evidence that this antioxidant peptide will be suitable as mitochondrial delivery vector.
Place, publisher, year, edition, pages
Stockholm: Department of Neurochemistry , 2015. , 47 p.
cell-penetrating peptide, mitochondrial targeting, ROS reduction, mitochondrial membrane potential, antioxidant activity
Research subject Neurochemistry with Molecular Neurobiology
IdentifiersURN: urn:nbn:se:su:diva-122082ISBN: 978-91-7649-312-0OAI: oai:DiVA.org:su-122082DiVA: diva2:864035
2015-11-30, Heilbronsalen, C458, Svante Arrhenius väg 16B, Stockholm, 14:00 (English)
Mäler, Lena, Professor
Langel, Ülo, Professor
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