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Department of Pharmacology

 
Author(s): 
Wu, Y, Kaur, A, Fowler, E, Wiedmann, MM, Young, R, Galloway, WRJD, Olsen, L, Sore, HF, Chattopadhyay, A, Kwan, TT-L, Xu, W, Walsh, SJ, de Andrade, P, Janecek, M, Arumugam, S, Itzhaki, LS, Lau, YH, Spring, DR
Abstract: 

Stapled peptides have great potential as modulators of protein-protein interactions (PPIs). However, there is a vast landscape of chemical features that can be varied for any given peptide, and identifying a set of features that maximizes cellular uptake and subsequent target engagement remains a key challenge. Herein, we present a systematic analysis of staple functionality on the peptide bioactivity landscape in cellular assays. Through application of a "toolbox" of diversified dialkynyl linkers to the stapling of MDM2-binding peptides via a double-click approach, we conducted a study of cellular uptake and p53 activation as a function of the linker. Minor changes in the linker motif and the specific pairing of linker with peptide sequence can lead to substantial differences in bioactivity, a finding which may have important design implications for peptide-based inhibitors of other PPIs. Given the complexity of the structure-activity relationships involved, the toolbox approach represents a generalizable strategy for optimization when progressing from in vitro binding assays to cellular efficacy studies.

Publication ID: 
1063483
Published date: 
15 March 2019
Publication source: 
manual
Publication type: 
Journal articles
Journal name: 
ACS Chem Biol
Publication volume: 
14
Publisher: 
Parent title: 
Edition: 
Publication number: