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

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 () and Anthony W. Partridge ()
Additional contact information
Arun Chandramohan: MSD International
Hubert Josien: Merck & Co., Inc.
Tsz Ying Yuen: Energy and Environment, Agency for Science, Technology and Research (ASTAR)
Ruchia Duggal: Merck & Co., Inc.
Diana Spiegelberg: Uppsala University
Lin Yan: Merck & Co., Inc.
Yu-Chi Angela Juang: MSD International
Lan Ge: Merck & Co., Inc.
Pietro G. Aronica: Agency for Science, Technology and Research (ASTAR)
Hung Yi Kristal Kaan: MSD International
Yee Hwee Lim: Energy and Environment, Agency for Science, Technology and Research (ASTAR)
Andrea Peier: Merck & Co., Inc.
Brad Sherborne: Merck & Co., Inc.
Jerome Hochman: Merck & Co., Inc.
Songnian Lin: Merck & Co., Inc.
Kaustav Biswas: Merck & Co., Inc.
Marika Nestor: Uppsala University
Chandra S. Verma: Agency for Science, Technology and Research (ASTAR)
David P. Lane: Institute of Molecular and Cell Biology
Tomi K. Sawyer: Merck & Co., Inc.
Robert Garbaccio: Merck & Co., Inc.
Brian Henry: MSD International
Srinivasaraghavan Kannan: Agency for Science, Technology and Research (ASTAR)
Christopher J. Brown: Institute of Molecular and Cell Biology
Charles W. Johannes: Energy and Environment, Agency for Science, Technology and Research (ASTAR)
Anthony W. Partridge: MSD International

Nature Communications, 2024, vol. 15, issue 1, 1-19

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-023-43346-4

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