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research article

Bulk measurement of membrane permeability for random cyclic peptides in living cells to guide drug development

Nielsen, Alexander L.  
•
Bartling, Christian R. O.
•
Zarda, Anne  
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March 7, 2025
Angewandte Chemie

Cyclic peptides are attractive for drug discovery due to their excellent binding properties and the potential to cross cell membranes. However, by far not all cyclic peptides are cell permeable, and measuring or predicting their membrane permeability is not trivial. In this work, we assessed the membrane permeability of thioether‐cyclized peptides, a widely used format in drug discovery. We developed a strategy for synthesizing hundreds of cyclic peptides carrying a short chloroalkane tag for the bulk quantification of membrane permeability in live cells using the chloroalkane penetration assay. Permeability data for random cyclic peptides established design rules, namely that the probability of peptides entering cells is strongly increasing if the molecular weight is below 800 Da, the polar surface is smaller than 250 Å2, or if there are less than six H‐bond donors. From this, machine learning could predict the membrane permeability of random peptides with good confidence, facilitating the future development of membrane permeable cyclic peptide drugs.

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Type
research article
DOI
10.1002/ange.202500493
Author(s)
Nielsen, Alexander L.  

École Polytechnique Fédérale de Lausanne

Bartling, Christian R. O.

University of Copenhagen Faculty of Science: Kobenhavns Universitet Det Natur- og Biovidenskabelige Fakultet Center for Biopharmaceuticals and Department of Drug Design and Pharmacology DENMARK

Zarda, Anne  

École Polytechnique Fédérale de Lausanne

De Sadeleer, Nathan Moïse  

EPFL

Neeser, Rebecca Manuela  

EPFL

Schwaller, Phillippe

École Polytechnique Fédérale de Lausanne

Strømgaard, Kristian

University of Copenhagen School of Global Health: Kobenhavns Universitet School of Global Health Center for Biopharmaceuticals and Department of Drug Design and Pharmacology DENMARK

Heinis, Christian  

EPFL

Date Issued

2025-03-07

Publisher

Wiley

Published in
Angewandte Chemie
Subjects

CAPA

•

chloroalkane tag

•

cyclic peptide

•

macrocycle

•

membrane permeability

Editorial or Peer reviewed

REVIEWED

Written at

EPFL

EPFL units
LPPT  
LIAC  
Available on Infoscience
May 12, 2025
Use this identifier to reference this record
https://infoscience.epfl.ch/handle/20.500.14299/249221.2
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