TY - JOUR
T1 - Toolbox of Diverse Linkers for Navigating the Cellular Efficacy Landscape of Stapled Peptides
AU - Wu, Yuteng
AU - Kaur, Amandeep
AU - Fowler, Elaine
AU - Wiedmann, Mareike M.
AU - Young, Reginald
AU - Galloway, Warren R.J.D.
AU - Olsen, Lasse
AU - Sore, Hannah F.
AU - Chattopadhyay, Anasuya
AU - Kwan, Terence T.L.
AU - Xu, Wenshu
AU - Walsh, Stephen J.
AU - De Andrade, Peterson
AU - Janecek, Matej
AU - Arumugam, Senthil
AU - Itzhaki, Laura S.
AU - Lau, Yu Heng
AU - Spring, David R.
PY - 2019/3/15
Y1 - 2019/3/15
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85061556846&partnerID=8YFLogxK
U2 - 10.1021/acschembio.9b00063
DO - 10.1021/acschembio.9b00063
M3 - Article
C2 - 30702850
AN - SCOPUS:85061556846
SN - 1554-8929
VL - 14
SP - 526
EP - 533
JO - ACS Chemical Biology
JF - ACS Chemical Biology
IS - 3
ER -