期刊
CHEMICAL SCIENCE
卷 7, 期 6, 页码 3694-3702出版社
ROYAL SOC CHEMISTRY
DOI: 10.1039/c5sc04048e
关键词
-
资金
- European Research Council [ERC-StG-240324]
- EPSRC [EP/P505593/1]
- Wellcome Trust [102577/Z/13/Z, 094232/Z/10/Z]
- BBSRC [BB/L015056/1]
- EPSRC [EP/K039202/1] Funding Source: UKRI
- Biotechnology and Biological Sciences Research Council [BB/L015056/1] Funding Source: researchfish
- Engineering and Physical Sciences Research Council [EP/K039202/1] Funding Source: researchfish
The development of constrained peptides represents an emerging strategy to generate peptide based probes and hits for drug-discovery that address challenging protein-protein interactions (PPIs). In this manuscript we report on the use of a novel alpha-alkenylglycine derived amino acid to synthesise hydrocarbon constrained BH3-family sequences (BIM and BID). Our biophysical and structural analyses illustrate that whilst the introduction of the constraint increases the population of the bioactive alpha-helical conformation of the peptide in solution, it does not enhance the inhibitory potency against proapoptotic Bcl-x(L) and Mcl-1 PPIs. SPR analyses indicate binding occurs via an induced fit mechanism whilst X-ray analyses illustrate none of the key interactions between the helix and protein are disturbed. The behaviour derives from enthalpy-entropy compensation which may be considered in terms of the ground state energies of the unbound constrained and unconstrained peptides; this has implications for the design of preorganised peptides to target protein-protein interactions.
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