1区 · 综合性期刊
ArticleOA
作者: Aronica, Pietro G ; Spiegelberg, Diana ; Kaan, Hung Yi Kristal ; Verma, Chandra S ; Garbaccio, Robert ; Lim, Yee Hwee ; Josien, Hubert ; Peier, Andrea ; Lin, Songnian ; Hochman, Jerome ; Kannan, Srinivasaraghavan ; Ge, Lan ; Sherborne, Brad ; Yan, Lin ; Yuen, Tsz Ying ; Brown, Christopher J ; Juang, Yu-Chi Angela ; Nestor, Marika ; Biswas, Kaustav ; Sawyer, Tomi K ; Duggal, Ruchia ; Partridge, Anthony W ; Lane, David P ; Chandramohan, Arun ; Johannes, Charles W ; Henry, Brian
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.
