Differential membrane binding of α/β-peptide foldamers: implications for cellular delivery and mitochondrial targeting
Tzong-Hsien Lee A , James W. Checco B G H , Tess Malcolm A I , Chelcie H. Eller C , Ronald T. Raines
B C , Samuel H. Gellman B , Erinna F. Lee D E F , W. Douglas Fairlie D E F and Marie-Isabel Aguilar A *
A Department of Biochemistry and Molecular Biology, Monash University, Clayton, Vic. 3800, Australia.
B Department of Chemistry, University of Wisconsin-Madison, Madison, WI 53706, USA.
C Department of Biochemistry, University of Wisconsin-Madison, Madison, WI 53706, USA.
D Department of Biochemistry and Chemistry, School of Agriculture, Biomedicine and Environment, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, Vic. 3086, Australia.
E Cell Death and Survival Laboratory, Olivia Newton-John Cancer Research Institute, Heidelberg, Vic. 3084, Australia.
F School of Cancer Medicine, La Trobe University, Melbourne, Vic. 3086, Australia.
G Present address: Department of Chemistry, University of Nebraska-Lincoln, Lincoln, NE 68588, USA.
H Present address: The Nebraska Center for Integrated Biomolecular Communication (NCIBC), University of Nebraska-Lincoln, Lincoln, NE 68588, USA.
I Present address: School of Chemistry, University of Melbourne, Parkville, Vic. 3052, Australia.
Australian Journal of Chemistry 76(8) 482-492 https://doi.org/10.1071/CH23063
Submitted: 29 March 2023 Accepted: 9 May 2023 Published: 14 June 2023
© 2023 The Author(s) (or their employer(s)). Published by CSIRO Publishing. This is an open access article distributed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (CC BY-NC-ND)
Abstract
The intrinsic pathway of apoptosis is regulated by the Bcl-2 family of proteins. Inhibition of the anti-apoptotic members represents a strategy to induce apoptotic cell death in cancer cells. We have measured the membrane binding properties of a series of peptides, including modified α/β-peptides, designed to exhibit enhanced membrane permeability to allow cell entry and improved access for engagement of Bcl-2 family members. The peptide cargo is based on the pro-apoptotic protein Bim, which interacts with all anti-apoptotic proteins to initiate apoptosis. The α/β-peptides contained cyclic β-amino acid residues designed to increase their stability and membrane permeability. Dual polarisation interferometry was used to study the binding of each peptide to two different model membrane systems designed to mimic either the plasma membrane or the outer mitochondrial membrane. The impact of each peptide on the model membrane structure was also investigated, and the results demonstrated that the modified peptides had increased affinity for the mitochondrial membrane and significantly altered the structure of the bilayer. The results also showed that the presence of an RRR motif significantly enhanced the ability of the peptides to bind to and insert into the mitochondrial membrane mimic, and provide insights into the role of selective membrane targeting of peptides.
Keywords: apoptosis, Bcl mimetics, dual polarisation interferometry, membrane permeability, membranes, mitochondrial membrane, peptides, peptidomimetics.
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