Thermodynamics of lipid interactions with cell-penetrating peptides

Sauder, Reto and Seelig, Joachim and Ziegler, André. (2011) Thermodynamics of lipid interactions with cell-penetrating peptides. Methods in Molecular Biology, 683. pp. 129-155.

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Official URL: http://edoc.unibas.ch/dok/A5842458

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Cationic peptides are efficiently taken up by biological cells through different pathways, which can be exploited for delivery of intracellular drugs. For example, their endocytosis is known since 1967, and this typically produces entrapment of the peptides in endocytotic vesicles. The resulting peptide (and cargo) degradation in lysosomes is of little therapeutic interest. Beside endocytosis (and various subtypes thereof), cationic cell-penetrating peptides (CPPs) may also gain access to cytosol and nucleus of livings cells. This process is known since 1988, but it is poorly understood whether the cytosolic CPP appearance requires an active cellular machinery with membrane proteins and signaling molecules, or whether this translocation occurs by passive diffusion and thus can be mimicked with model membranes devoid of proteins or glycans. In the present chapter, protocols are presented that allow for testing the membrane binding and disturbance of CPPs on model membranes with special focus on particular CPP properties. Protocols include vesicle preparation, lipid quantification, and analysis of membrane leakage, lipid polymorphism ((31)P NMR), and membrane binding (isothermal titration calorimetry). Using these protocols, a major difference among CPPs is observed: At low micromolar concentration, nonamphipathic CPPs, such as nona-arginine (WR(9)) and penetratin, have only a poor affinity for model membranes with a lipid composition typical of eukaryotic membranes. No membrane leakage is induced by these compounds at low micromolar concentration. In contrast, their amphipathic derivatives, such as acylated WR(9) (C(14), C(16), C(18)) or amphipathic penetratin mutant p2AL (Drin et al., Biochemistry 40:1824-1834, 2001), bind and disturb lipid model membranes already at low micromolar peptide concentration. This suggests that the mechanism for cytosolic CPP delivery (and potential toxicity) differs among CPPs despite their common name.
Faculties and Departments:05 Faculty of Science > Departement Biozentrum > Former Organization Units Biozentrum > Biophysical Chemistry (Seelig J)
UniBasel Contributors:Seelig, Joachim
Item Type:Article, refereed
Article Subtype:Research Article
Publisher:Humana Press
Note:Publication type according to Uni Basel Research Database: Journal article
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Last Modified:14 Nov 2017 12:41
Deposited On:14 Sep 2012 06:41

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