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.
| Original language | English |
|---|---|
| Pages (from-to) | 526-533 |
| Number of pages | 8 |
| Journal | ACS Chemical Biology |
| Volume | 14 |
| Issue number | 3 |
| DOIs | |
| Publication status | Published - 15 Mar 2019 |
| Externally published | Yes |
Cite this
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Toolbox of Diverse Linkers for Navigating the Cellular Efficacy Landscape of Stapled Peptides. / Wu, Yuteng; Kaur, Amandeep; Fowler, Elaine; Wiedmann, Mareike M.; Young, Reginald; Galloway, Warren R.J.D.; Olsen, Lasse; Sore, Hannah F.; Chattopadhyay, Anasuya; Kwan, Terence T.L.; Xu, Wenshu; Walsh, Stephen J.; De Andrade, Peterson; Janecek, Matej; Arumugam, Senthil; Itzhaki, Laura S.; Lau, Yu Heng; Spring, David R.
In: ACS Chemical Biology, Vol. 14, No. 3, 15.03.2019, p. 526-533.Research output: Contribution to journal › Article › Research › peer-review
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
VL - 14
SP - 526
EP - 533
JO - ACS Chemical Biology
JF - ACS Chemical Biology
SN - 1554-8929
IS - 3
ER -