AIMMS Seminar: Roland Brock, PhD

11/15/2017

16.00 - 17.00h

Room 01W08, O|2 Lab Building

AIMMS Seminar: Cell-penetrating peptides - Understanding the principles of cytosolic delivery

Roland Brock, PhD (Radboud University)

Amsterdam Institute for Molecules, Medicines and Systems

Sciences

Seminar

Roland Brock, PhD (Radboud University) will provide an AIMMS Seminar on 15 November entitled 'Cell-penetrating peptides - Understanding the principles of cytosolic delivery'.

You are all cordially invited!

Abstract

Cell-penetrating peptides (CPPs) are a highly promising class of delivery vectors to enhance the cytosolic uptake of molecules that otherwise do not enter cells. However, in most cases uptake occurs by endocytosis and cargo peptide complexes are trapped in the endolysosomal pathway. Cytosolic delivery can occur either by direct crossing of the plasma membrane or by induction of endosomal release.

I will summarize our insights into the structural and mechanistic principles of direct membrane permeation highlighting the role of the membrane lipid composition, transmembrane potential and intracellular calcium signaling. In general, direct membrane permeation is restricted to arginine-rich peptides and not observed for amphipathic peptides. Next to high sphingomyelin content, unpublished data also implicates the actin cytoskeleton as a factor in membrane resistance.

However, a recent study on hydrocarbon stapled peptides demonstrated that also from the endolysosomal compartment leakage occurs and leads to cytosolic accumulation of peptide, given that the peptide is sufficiently stable and captured through interaction with target proteins. By comparison, very different structural principles govern the activity of CPPs in oligonucleotide delivery. In this case, activity is restricted to more membrane active amphipathic peptides and involves endocytosis.

Literature

  • Duchardt, F., Fotin-Mleczek, M., Schwarz, H. Fischer, R., Brock, R., A comprehensive model for the cellular uptake of cationic cell-penetrating peptides, Traffic, 8 (2007) 848-866
  • van Asbeck, A. H., Beyerle, A., McNeill, H., Bovee-Geurts, P. H., Lindberg, S., Verdurmen, W. P., Hallbrink, M., Langel, U., Heidenreich, O., Brock, R., Molecular parameters of siRNA-cell penetrating peptide nanocomplexes for efficient cellular delivery, ACS Nano, 7 (2013) 3797-3807
  • Wallbrecher, R., Ackels, T., Olea A. R., Klein, M. J., Caillon, L., Schiller, J., Bovée-Geurts, P. H., van Kuppevelt, T. H., Ulrich, A. S., Spehr, M., Adjobo-Hermans, M. J. W., Brock, R., Membrane permeation of arginine-rich cell-penetrating peptides independent of transmembrane potential as a function of lipid composition and membrane fluidity. J. Control. Release. 256 (2017) 68-78
  • Wallbrecher, R., Chène, P., Ruetz, S., Stachyra, T., Vorherr, T., Brock, R., A critical assessment of the synthesis and biological activity of p53/Hdm2 stapled peptide inhibitors. Br. J. Pharmacol. 174 (2017) 2613-2622