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Effect of a Fusion Peptide by Covalent Conjugation of a Mitochondrial Cell-Penetrating Peptide and a Glutathione Analog Peptide
Stockholm University, Faculty of Science, Department of Neurochemistry.
Stockholm University, Faculty of Science, Department of Neurochemistry. University of Tartu, Estonia.
Number of Authors: 22017 (English)In: Molecular therapy. Methods & clinical development, ISSN 2399-6951, E-ISSN 2329-0501, Vol. 5, p. 221-231Article in journal (Refereed) Published
Abstract [en]

Previously, we designed and synthesized a library of mitochondrial antioxidative cell-penetrating peptides (mtCPPs) superior to the parent peptide, SS31, to protect mitochondria from oxidative damage. A library of antioxidative glutathione analogs called glutathione peptides (UPFs), exceptional in hydroxyl radical elimination compared with glutathione, were also designed and synthesized. Here, a follow-up study is described, investigating the effects of the most promising members from both libraries on reactive oxidative species scavenging ability. None of the peptides influenced cell viability at the concentrations used. Fluorescence microscopy studies showed that the fluorescein-mtCPP1-UPF25 (mtgCPP) internalized into cells, and spectrofluorometric analysis determined the presence and extent of peptide into different cell compartments. mtgCPP has superior antioxidative activity compared with mtCPP1 and UPF25 against H2O2 insult, preventing ROS formation by 2- and 3-fold, respectively. Moreover, we neither observed effects on mitochondrial membrane potential nor production of ATP. These data indicate that mtgCPP is targeting mitochondria, protecting them from oxidative damage, while also being present in the cytosol. Our hypothesis is based on a synergistic effect resulting from the fused peptide. The mitochondrial peptide segment is targeting mitochondria, whereas the glutathione analog peptide segment is active in the cytosol, resulting in increased scavenging ability.

Place, publisher, year, edition, pages
2017. Vol. 5, p. 221-231
Keywords [en]
antioxidants, cell-penetrating peptides, glutathione analogs, superoxide anion scavenging, mitochondrial targeting, mitochondrial membrane potential
National Category
Biological Sciences
Research subject
Neurochemistry with Molecular Neurobiology
Identifiers
URN: urn:nbn:se:su:diva-145999DOI: 10.1016/j.omtm.2017.04.010ISI: 000406299600022PubMedID: 28567432OAI: oai:DiVA.org:su-145999DiVA, id: diva2:1136269
Available from: 2017-08-26 Created: 2017-08-26 Last updated: 2018-04-16Bibliographically approved
In thesis
1. Cell-Penetrating Peptides for Mitochondrial Targeting
Open this publication in new window or tab >>Cell-Penetrating Peptides for Mitochondrial Targeting
2018 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Mitochondria have simply been known as the cell’s powerhouse for a long time, with its vital function of producing ATP. However, substantially more attention was directed towards these organelles once they were recognized to perform several essential functions having an impact in cell biology, pharmaceutics and medicine. Dysfunctions of these organelles have been linked to several diseases such as diabetes, cancer, neurodegenerative diseases and cardiovascular disorders. Mitochondrial medicine emerged once the relationship of reactive oxygen species and mutations of the mitochondrial DNA linked to diseases was shown, referred to as mitochondrial dysfunction. This has led to the need to deliver therapeutic molecules in their active form not only to the target cells but more importantly into the targeted organelles.

In this thesis, cell-penetrating peptides (CPPs) used as mitochondrial drug delivery system and the pathways involved in the uptake mechanisms of a CPP are described. In particular, Paper I describes a novel cell-penetrating peptide targeting mitochondria with intrinsic antioxidant properties. Paper II expands upon this first finding and show that the same peptide can carry a glutathione analogue peptide with improved radical scavenging ability into cytoplasm and mitochondria. Paper III introduces mitochondrial targeting peptides for delivery of therapeutic biomolecules to modify mitochondrial gene expression. In Paper IV, the uptake mechanisms of the CPP delivery strategy has been investigated to gain a better understanding of the used transfection system.

Overall, this thesis summarizes our current effort regarding cell-penetrating peptides delivery system to target mitochondria and the progress made towards a potential gene therapy. It contributes to the field of CPPs and drug delivery with a set of peptides with radical scavenging ability, a strategy to deliver oligonucleotides to mitochondria as proof-of-concept for mitochondrial gene therapy, and to help understanding the pathways involved in CPPs uptake.

Place, publisher, year, edition, pages
Stockholm: Department of Biochemistry and Biophysics, Stockholm University, 2018. p. 62
Keywords
Mitochondrial targeting, cell-penetrating peptides, antioxidant activity, scavenging ability, oligonucleotide delivery
National Category
Biochemistry and Molecular Biology
Research subject
Neurochemistry with Molecular Neurobiology
Identifiers
urn:nbn:se:su:diva-155156 (URN)978-91-7797-230-3 (ISBN)978-91-7797-231-0 (ISBN)
Public defence
2018-06-01, Magnélisalen, Kemiska övningslaboratoriet, Svante Arrhenius väg 16 B, Stockholm, 10:00 (English)
Opponent
Supervisors
Note

At the time of the doctoral defense, the following paper was unpublished and had a status as follows: Paper 3: Manuscript.

Available from: 2018-05-08 Created: 2018-04-13 Last updated: 2018-05-04Bibliographically approved

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