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

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

SUBMITTER: Chandramohan A 

PROVIDER: S-EPMC10786919 | biostudies-literature | 2024 Jan

REPOSITORIES: biostudies-literature