Azzarito Valeria, Miles Jennifer A, Fisher Julie, Edwards Thomas A, Warriner Stuart L, Wilson Andrew J
School of Chemistry , University of Leeds , Woodhouse Lane , Leeds , LS2 9JT , UK . Email:
Astbury Centre for Structural and Molecular Biology , University of Leeds , Woodhouse Lane , Leeds , LS2 9JT , UK.
Chem Sci. 2015 Apr 1;6(4):2434-2443. doi: 10.1039/c4sc03559c. Epub 2015 Jan 30.
The development of foldamers capable of selective molecular recognition of solvent exposed protein surfaces represents an outstanding challenge in supramolecular chemical biology. Here we introduce an oligoamide foldamer with well-defined conformation that bears all the hallmarks of an information rich oligomer. Specifically, the foldamer recognizes its target protein DM2 leading to inhibition of its protein-protein interaction with p53 in a manner that depends upon the composition, spatial projection and stereochemistry of functional groups appended to the scaffold. Most significantly, selective inhibition of p53/DM2 can be achieved against four other targets and the selectivity for p53/DM2 inhibition Mcl-1/NOXA-B inhibition is critically dependent upon the stereochemistry of the helix mimetic.
能够对溶剂暴露的蛋白质表面进行选择性分子识别的折叠体的开发是超分子化学生物学中的一项重大挑战。在此，我们介绍一种具有明确构象的寡酰胺折叠体，它具有富含信息的寡聚物的所有特征。具体而言，该折叠体识别其靶蛋白DM2，从而以一种取决于连接到支架上的官能团的组成、空间投影和立体化学的方式抑制其与p53的蛋白质-蛋白质相互作用。最重要的是，针对其他四个靶标可实现对p53/DM2的选择性抑制，并且对p53/DM2抑制的选择性（相对于Mcl-1/NOXA-B抑制）关键取决于螺旋模拟物的立体化学。
