Helical β-peptide inhibitors of the p53-hDM2 interaction
Helical β-peptide inhibitors of the p53-hDM2 interaction
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DOI：
10.1021/ja031625a
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发表时间：
2004-08-11
影响因子：
15
通讯作者：
Schepartz, A
中科院分区：
文献类型：
--
作者：
Kritzer, JA;Lear, JD;Schepartz, A
hDM 2在体内被p53反式激活结构域（p53 AD）内的短α-螺旋识别。破坏p53·hDM 2相互作用是癌症治疗的重要目标。由p53 AD螺旋的一面上的三个残基（F19、W23和L26）组成的功能性表位对结合自由能有很大贡献。我们假设，如果F19、W23和L26的侧链在稳定的β3肽14-螺旋上相隔三个残基的连续位置处呈递，则p53 AD功能表位将被重现。在这里，我们报告了一组在水中具有显著的14螺旋结构的β3肽;人们以纳摩尔亲和力识别hDM 2表面上的裂缝。我们描述的β3肽设计策略是通用的，并且可能比将单个或多个β氨基酸取代引入功能性α肽的策略具有优势，因为它是基于二级结构水平的同源性，而不是一级序列。
hDM2 is recognized in vivo by a short α-helix within the p53 trans-activation domain (p53AD). Disruption of the p53·hDM2 interaction is an important goal for cancer therapy. A functional epitope comprised of three residues on one face of the p53AD helix (F19, W23, and L26) contributes heavily to the binding free energy. We hypothesized that the p53AD functional epitope would be recapitulated if the side chains of F19, W23, and L26 were presented at successive positions three residues apart on a stabilized β3-peptide 14-helix. Here, we report a set of β3-peptides that possess significant 14-helix structure in water; one recognizes a cleft on the surface of hDM2 with nanomolar affinity. The strategy for β3-peptide design that we describe is general and may have advantages over one in which individual or multiple β-amino acid substitutions are introduced into a functional α-peptide, because it is based on homology at the level of secondary structure, not primary sequence.