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Bulk Measurement of Membrane Permeability for Random Cyclic Peptides in Living Cells to Guide Drug Development
Alexander L Nielsen1, Christian R O Bartling2, Anne Zarda1
1Institute of Chemical Sciences and Engineering, School of Basic Sciences, École Polytechnique Fédérale de Lausanne (EPFL), Lausanne, CH-1015, Switzerland.
Angewandte Chemie (International Ed. in English)
|March 7, 2025
Summary
Researchers developed a method to measure cyclic peptide cell permeability. Key factors for cell entry include molecular weight under 800 Da, polar surface area below 250 Ų, and fewer than six hydrogen bond donors.
Area of Science:
- Medicinal Chemistry
- Biotechnology
- Pharmacology
Background:
- Cyclic peptides show promise for drug discovery due to strong binding and potential cell membrane penetration.
- However, predicting and measuring the cell membrane permeability of cyclic peptides remains a challenge.
Purpose of the Study:
- To assess the membrane permeability of thioether-cyclized peptides, a common format in drug discovery.
- To establish design rules for enhancing cyclic peptide cell permeability.
Main Methods:
- Developed a synthesis strategy for hundreds of cyclic peptides with a chloroalkane tag.
- Utilized a chloroalkane penetration assay for bulk quantification of membrane permeability in live cells.
Main Results:
- Identified key design rules for cell permeability: molecular weight < 800 Da, polar surface area < 250 Ų, and < 6 hydrogen bond donors.
- Machine learning models accurately predicted peptide membrane permeability based on these rules.
Conclusions:
- Established clear design principles for creating cell-permeable cyclic peptides.
- Machine learning prediction facilitates the development of cyclic peptide-based therapeutics.
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