Reversible activation of a cell-penetrating peptide in a membrane environment.
Cell-penetrating peptides (CPPs) are promising molecules as drug carriers. However, because their uptake mainly involves endocytic mechanisms, endosomal trapping of the carrier (and drug) remains a high barrier for biomedical applications. The viral fusion mimic GALA, a pH-triggered CPP, takes advantage of the decreasing pH during endosome maturation to selectively attack endosomal membranes. Below pH 6, the sequence folds into a helix and can disrupt membranes. In this study, we show that the lipid bilayer radius-of-curvature has a negligible effect on GALA-induced leakage kinetics and that GALA remains pH responsive after inserting into a lipid membrane. The peptide can be reversibly "switched" between its inactive and active states after incorporation into the hydrophobic environment of lipid membranes, even after substantially interacting with lipid chains. This ability makes GALA-based delivery a potentially safe and efficient strategy for endosomal escape.
Department of Molecular Spectroscopy, Max Planck Institute for Polymer Research , Mainz 55128, Germany.
Denise K
DK
Schach
Department of Molecular Spectroscopy, Max Planck Institute for Polymer Research , Mainz 55128, Germany.
William
W
Rock
Department of Molecular Spectroscopy, Max Planck Institute for Polymer Research , Mainz 55128, Germany.
Johannes
J
Franz
Department of Molecular Spectroscopy, Max Planck Institute for Polymer Research , Mainz 55128, Germany.
Mischa
M
Bonn
Department of Molecular Spectroscopy, Max Planck Institute for Polymer Research , Mainz 55128, Germany.
Sapun H
SH
Parekh
Department of Molecular Spectroscopy, Max Planck Institute for Polymer Research , Mainz 55128, Germany.
Tobias
T
Weidner
D057846:Cell-Penetrating Peptides / Q000737:chemistry / Q000378:metabolism*; D011992:Endosomes / Q000737:chemistry / Q000378:metabolism*; D006863:Hydrogen-Ion Concentration; D057927:Hydrophobic and Hydrophilic Interactions; D008051:Lipid Bilayers / Q000737:chemistry / Q000378:metabolism*
D057846:Cell-Penetrating Peptides; D008051:Lipid Bilayers