학술논문
Design-rules for stapled peptides with in vivo activity and their application to Mdm2/X antagonists
Document Type
article
Author
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
Source
Nature Communications, Vol 15, Iss 1, Pp 1-19 (2024)
Subject
Language
English
ISSN
2041-1723
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.