Lactam-Stapled Cell-Penetrating Peptides Cell Uptake and Membrane Binding Properties
Klein, M.J., Schmidt, S., Wadhwani, P., Bürck, J., Reichert, J., Afonin, S., Berditsch, M., Schober, T., Brock, R., Kansy, M., Ulrich, A.S.
Stapling of side chains to stabilize an α-helical structure has been generally associated with an increased uptake of CPPs. Here, we compare
four amphiphilic stapled peptides with their linear counterparts in terms of their membrane binding and conformational features in order to correlate these with uptake efficiency
and toxicological effects. The impact of lactam stapling was found to vary strongly with regard to the different aspects of peptide-membrane interactions. Nearly all stapled
peptides caused less membrane perturbation (vesicle leakage, hemolysis, bacterial lysis) than their linear counterparts. In one case (MAP-1) where stapling enhanced
α-helicity in aqueous and lipid environments, leakage was eliminated while cell uptake in HEK293 and HeLa cells remained high, which improved the overall characteristics.
The other systems (DRIM, WWSP, KFGF) did not improve, however. The data suggest that cell uptake of amphipathic CPPs correlates with their adopted α-helix content in
membranes rather than their helicity in solution.