| Autor: |
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 |
| Jazyk: |
angličtina |
| Rok vydání: |
2024 |
| Předmět: |
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| Zdroj: |
Nature Communications, Vol 15, Iss 1, Pp 1-19 (2024) |
| Druh dokumentu: |
article |
| ISSN: |
2041-1723 |
| DOI: |
10.1038/s41467-023-43346-4 |
| Popis: |
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. |
| Databáze: |
Directory of Open Access Journals |
| Externí odkaz: |
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