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Is the Mirror Image a True Reflection? Intrinsic Membrane Chirality Modulates Peptide Binding.
Sónia Troeira Henriques1,2, Hayden Peacock1, Aurélie H Benfield1,2
1Institute for Molecular Bioscience , The University of Queensland , Brisbane , Queensland 4072 , Australia.
Journal of the American Chemical Society
|November 26, 2019
Summary
Chirality matters for drug action. This study reveals that the chiral environment of cell membranes influences how membrane-active peptides, like kalata B1, bind, challenging previous assumptions.
Area of Science:
- Biochemistry
- Molecular Pharmacology
- Membrane Biophysics
Background:
- Peptides are promising drug leads, but their mechanism of action requires elucidation for clinical use.
- Chiral analysis of peptides (native vs. enantiomer) is a standard method to distinguish membrane- vs. receptor-mediated actions.
- This method assumes peptide-lipid interactions are independent of chirality.
Purpose of the Study:
- To investigate the role of chirality in peptide-lipid interactions.
- To challenge the paradigm that peptide-membrane interactions are achiral.
- To explore the influence of the lipid bilayer's chiral environment on peptide function.
Main Methods:
- Synthesis of phospholipids with non-natural chirality to create mirror-image model membranes.
- Comparative analysis of native cyclotide kalata B1 and its enantiomer binding to these model membranes.
- Affinity measurements to quantify peptide-lipid interactions.
Main Results:
- Native kalata B1 exhibited higher binding affinity to phospholipids mirroring the chirality of eukaryotic membranes.
- The enantiomer of kalata B1 showed reduced binding potency compared to the native peptide.
- Demonstrated that peptide-lipid binding is sensitive to the chirality of the lipid bilayer.
Conclusions:
- The chiral environment of lipid bilayers can significantly modulate the function of membrane-active peptides.
- This finding challenges the long-held assumption that peptide-lipid interactions are achiral.
- Highlights the importance of considering lipid chirality in drug design and understanding peptide mechanisms of action.
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