Lau Yu Heng, de Andrade Peterson, McKenzie Grahame J, Venkitaraman Ashok R, Spring David R
University Chemical Laboratory, University of Cambridge, Lensfield Road, Cambridge CB2 1EW (UK).
Chembiochem. 2014 Dec 15;15(18):2680-3. doi: 10.1002/cbic.201402374. Epub 2014 Oct 29.
We investigated linear aliphatic dialkynes as a new structural class of i,i+7 linkers for the double-click stapling of p53-based peptides. The optimal combination of azido amino acids and dialkynyl linker length for MDM2 binding was determined. In a direct comparison between aliphatic and aromatic staple scaffolds, the aliphatic staples resulted in superior binding to MDM2 in vitro and superior p53-activating capability in cells when using a diazidopeptide derived from phage display. This work demonstrates that the nature of the staple scaffold is an important factor that can affect peptide bioactivity in cells.
我们研究了线性脂肪族二炔，将其作为用于基于p53的肽的双点击钉合的新型i,i+7连接体结构类别。确定了用于MDM2结合的叠氮基氨基酸和二炔基连接体长度的最佳组合。在脂肪族和芳香族钉合支架的直接比较中，当使用源自噬菌体展示的二叠氮肽时，脂肪族钉合在体外对MDM2的结合能力更强，在细胞中的p53激活能力也更强。这项工作表明，钉合支架的性质是一个可影响细胞中肽生物活性的重要因素。
