Design-rules for stapled peptides with in vivo activity and their application to Mdm2/X antagonists

Design-rules for stapled peptides with in vivo activity and their application to Mdm2/X antagonists

Nature Communications

10.1038/s41467-023-43346-4

https://doi.org/10.1038/s41467-023-43346-4

Arun Chandramohan, Hubert Josien, Tsz Ying Yuen, Ruchia Duggal, Diana Spiegelberg, Lin Yan, Yu-Chi Angela Juang, Lan Ge, Pietro G. Aronica, Hung Yi Kristal Kaan, Yee Hwee Lim, Andrea Peier, Brad Sherborne, Jerome Hochman, Songnian Lin, Kaustav Biswas, Marika Nestor, Chandra S. Verma, David P. Lane, Tomi K. Sawyer, Robert Garbaccio, Brian Henry, Srinivasaraghavan Kannan, Christopher J. Brown, Charles W. Johannes, Anthony W. Partridge

Breast cancer, peptides

12 January 2024

Chandramohan, A., Josien, H., Yuen, T. Y., Duggal, R., Spiegelberg, D., Yan, L., Juang, Y.-C. A., Ge, L., Aronica, P. G., Kaan, H. Y. K., Lim, Y. H., Peier, A., Sherborne, B., Hochman, J., Lin, S., Biswas, K., Nestor, M., Verma, C. S., Lane, D. P., … Partridge, A. W. (2024). Design-rules for stapled peptides with in vivo activity and their application to Mdm2/X antagonists. Nature Communications, 15(1). https://doi.org/10.1038/s41467-023-43346-4

Abstract Although stapled α-helical peptides can address challenging targets, their advancement is impeded by poor understandings for making them cell permeable while avoiding off-target toxicities. By synthesizing >350 molecules, we present workflows for identifying stapled peptides against Mdm2(X) with in vivo activity and no off-target effects. Key insights include a clear correlation between lipophilicity and permeability, removal of positive charge to avoid off-target toxicities, judicious anionic residue placement to enhance solubility/behavior, optimization of C-terminal length/helicity to enhance potency, and optimization of staple type/number to avoid polypharmacology. Workflow application gives peptides with >292x improved cell proliferation potencies and no off-target cell proliferation effects ( > 3800x on-target index). Application of these ‘design rules’ to a distinct Mdm2(X) peptide series improves ( > 150x) cellular potencies and removes off-target toxicities. The outlined workflow should facilitate therapeutic impacts, especially for those targets such as Mdm2(X) that have hydrophobic interfaces and are targetable with a helical motif.

Attribution 4.0 International (CC BY 4.0)

This research / project is supported by the Agency for Science, Technology and Research (A*STAR) - Singapore Industry Alignment Fund-Pre-Positioning (IAF-PP) grant
Grant Reference no. : H1701a0010

This research / project is supported by the Agency for Science, Technology and Research (A*STAR) - Singapore Industry Alignment Fund-Industry Collaboration Project (IAF-ICP) grant
Grant Reference no. : I1901E0039

https://oar.a-star.edu.sg/communities-collections/articles/22202

2041-1723

Bioinformatics Institute