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Secondary Structure of Cell-Penetrating Peptides Controls Membrane Interaction and Insertion
Stockholm University, Faculty of Science, Department of Neurochemistry.
Stockholm University, Faculty of Science, Department of Neurochemistry. University of Tartu, Estonia.ORCID iD: 0000-0001-6107-0844
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2010 (English)In: Biochimica et Biophysica Acta - Biomembranes, ISSN 0005-2736, E-ISSN 1879-2642, Vol. 1798, no 6, 1119-1128 p.Article in journal (Refereed) Published
Abstract [en]

The clinical use of efficient therapeutic agents is often limited by the poor permeability of the biological membranes. In order to enhance their cell delivery, short amphipathic peptides called cell-penetrating peptides (CPPs) have been intensively developed for the last two decades. CPPs are based either on protein transduction domains, model peptide or chimeric constructs and have been used to deliver cargoes into cells through either covalent or non-covalent strategies. Although several parameters are simultaneously involved in their internalization mechanism, recent focuses on CPPs suggested that structural properties and interactions with membrane phospholipids could play a major role in the cellular uptake mechanism. In the present work, we report a comparative analysis of the structural plasticity of 10 well-known CPPs as well as their ability to interact with phospholipid membranes. We propose a new classification of CPPs based on their structural properties, affinity for phospholipids and internalization pathways already reported in the literature.

Place, publisher, year, edition, pages
2010. Vol. 1798, no 6, 1119-1128 p.
Keyword [en]
Cell-penetrating peptides, Structure, Membrane interactions, Conformation, Versatility
National Category
Biochemistry and Molecular Biology
URN: urn:nbn:se:su:diva-39079DOI: 10.1016/j.bbamem.2010.03.005ISI: 000278321200012OAI: diva2:318333
Available from: 2010-05-07 Created: 2010-05-07 Last updated: 2015-04-21Bibliographically approved
In thesis
1. Structures, toxicity and internalization of cell-penetrating peptides
Open this publication in new window or tab >>Structures, toxicity and internalization of cell-penetrating peptides
2010 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Cellular internalization is a highly regulated process controlled by proteins in the plasma membrane. Large and hydrophilic compounds, in particular, face difficulties conquering the plasma membrane barrier in order to gain access to intracellular environment. This puts serious constrains on the drug industry since many drugs are hydrophilic. Several methods aiming at aiding the cellular internalization of otherwise impermeable compounds have therefore been developed. One such class, so-called cell-penetrating peptides (CPPs), emerged around twenty years ago. This group constitutes hundreds of peptides that have shown a remarkable ability in translocating diverse molecules, ranging from small molecules to large proteins, over the cell membrane. The internalization mechanism of CPPs has been questioned ever since the first peptides were discovered. Initially, the consensus in the field was direct translocation but endocytosis has gradually gained ground. The confusion and the disunity within this research field through the years proceeds from divergent results between research groups that hamper comparison of the peptides.

This thesis aims at characterizing several well-established CPPs with comprehensive studies on cellular toxicity, secondary structure and cellular internalization kinetics.

The results demonstrate that CPPs act in general in a low or non-toxic way, but the apparent toxicity is both peptide- and cell line-dependent. Structural studies show that the CPPs have a diverse polymorphic behavior ranging from random coil to structured β-sheet or α-helix, depending on the environment. The ability to change secondary structure could be the key to the internalization property of the CPPs. Internalization kinetic studies of CPP conjugates reveal two sorts of internalization profiles, either fast curves that cease in few minutes or slow curves that peak in tens of minutes. Furthermore, improved synthesis of CPP conjugates is demonstrated.

In conclusion, the studies in this thesis provide useful information about cytotoxicity and structural diversity of CPPs, and emphasize the importance of kinetic measurements over end-point studies in order to give better insights into the internalization mechanisms of CPPs.

Place, publisher, year, edition, pages
Stockholm: Department of Neurochemistry, Stockholms University, 2010. 54 p.
CPP, cell-penetrating peptide, internalization, toxicity, structures
National Category
Research subject
Neurochemistry with Molecular Neurobiology
urn:nbn:se:su:diva-38607 (URN)978-91-7447-058-1 (ISBN)
Public defence
2010-06-04, Magnélisalen, Kemiska övningslaboratoriet, Svante Arrhenius väg 16 B, Stockholm, 10:00 (English)

At the time of the doctoral defense, the following paper was unpublished and had a status as follows: Paper 4: Submitted.

Available from: 2010-05-11 Created: 2010-04-20 Last updated: 2015-03-11Bibliographically approved

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Eiríksdóttir, EmelíaLangel, Ülo
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