@article{nielsen_bulk_2025,
	title = {Bulk {Measurement} of {Membrane} {Permeability} for {Random} {Cyclic} {Peptides} in {Living} {Cells} to {Guide} {Drug} {Development}},
	issn = {1433-7851, 1521-3773},
	url = {https://onlinelibrary.wiley.com/doi/10.1002/anie.202500493},
	doi = {10.1002/anie.202500493},
	abstract = {Abstract 
             
              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, indicating the probability of peptides entering cells is strongly increasing if the molecular weight is below 800 Da, the polar surface is smaller than 250 Å 
              2 
              , or if there are less than six hydrogen 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.},
	language = {en},
	urldate = {2025-06-19},
	journal = {Angewandte Chemie International Edition},
	author = {Nielsen, Alexander L. and Bartling, Christian R. O. and Zarda, Anne and De Sadeleer, Nathan and Neeser, Rebecca M. and Schwaller, Phillippe and Strømgaard, Kristian and Heinis, Christian},
	month = jun,
	year = {2025},
	pages = {e202500493},
}