Design-rules for stapled peptides with in vivo activity and their application to Mdm2/X antagonists
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Published:2024-01-12
Issue:1
Volume:15
Page:
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ISSN:2041-1723
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Container-title:Nature Communications
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language:en
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Short-container-title:Nat Commun
Author:
Chandramohan Arun, Josien Hubert, Yuen Tsz Ying, Duggal Ruchia, Spiegelberg DianaORCID, Yan Lin, Juang Yu-Chi Angela, Ge Lan, Aronica Pietro G.ORCID, Kaan Hung Yi Kristal, Lim Yee Hwee, Peier Andrea, Sherborne Brad, Hochman Jerome, Lin Songnian, Biswas Kaustav, Nestor MarikaORCID, Verma Chandra S.ORCID, Lane David P., Sawyer Tomi K., Garbaccio Robert, Henry BrianORCID, Kannan SrinivasaraghavanORCID, Brown Christopher J., Johannes Charles W.ORCID, Partridge Anthony W.ORCID
Abstract
AbstractAlthough 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.
Publisher
Springer Science and Business Media LLC
Subject
General Physics and Astronomy,General Biochemistry, Genetics and Molecular Biology,General Chemistry,Multidisciplinary
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