Chemistry
Document Type
Article
Abstract
Macrocycle peptides are promising constructs for imaging and inhibiting extracellular, and cell membrane proteins, but their use for targeting intracellular proteins is typically limited by poor cell penetration. We report the development of a cell-penetrant high-affinity peptide ligand targeted to the phosphorylated Ser474 epitope of the (active) Akt2 kinase. This peptide can function as an allosteric inhibitor, an immunoprecipitation reagent, and a live cell immunohistochemical staining reagent. Two cell penetrant stereoisomers were prepared and shown to exhibit similar target binding affinities and hydrophobic character but 2-3-fold different rates of cell penetration. Experimental and computational studies resolved that the ligands’ difference in cell penetration could be assigned to their differential interactions with cholesterol in the membrane. These results expand the tool kit for designing new chiral-based cell-penetrant ligands. © 2023, The Author(s).
Publication Title
Communications Chemistry
Publication Date
12-2023
Volume
6
Issue
1
ISSN
2399-3669
DOI
10.1038/s42004-023-00890-w
Keywords
macrocycle peptides, peptides, menbrane, Akt2
Repository Citation
Nag, Arundhati; Mafi, Amirhossein; Das, Samir; Yu, Mary Beth; Alvarez-Villalonga, Belen; Kim, Soo-Kyung; Su, Yapeng; Goddard, William A.; and Heath, James R., "Stereochemical engineering yields a multifunctional peptide macrocycle inhibitor of Akt2 by fine-tuning macrocycle-cell membrane interactions" (2023). Chemistry. 11.
https://commons.clarku.edu/chemistry/11
Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 International License.
Copyright
© The Author(s) 2023.