期刊
ACS CHEMICAL BIOLOGY
卷 14, 期 3, 页码 526-533出版社
AMER CHEMICAL SOC
DOI: 10.1021/acschembio.9b00063
关键词
-
资金
- ERC
- EPSRC
- BBSRC
- MRC [G1002329]
- Royal Society
- Cambridge Trusts
- Cancer Research UK
- Department of Chemistry at the University of Cambridge
- Cambridge Cancer Centre
- AstraZeneca
- Conselho Nacional de Desenvolvimento Cientifico e Tecnologico
- Senior Fellowship from the Medical Research Foundation
- School of the Physical Sciences
- Cancer Research UK [27225, 22676] Funding Source: researchfish
- Medical Research Council [G1002329] Funding Source: researchfish
- Medical Research Foundation [C0385] Funding Source: researchfish
- EPSRC [1800602, EP/P020291/1] Funding Source: UKRI
- MRC [G1002329] Funding Source: UKRI
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.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据