α-Helix mimicry with α/β-peptides.
α-Helix mimicry with α/β-peptides.
复制标题
DOI：
10.1016/b978-0-12-394292-0.00019-9
复制
发表时间：
2013
影响因子：
--
通讯作者：
Gellman, Samuel H.
中科院分区：
文献类型：
--
作者：
Johnson, Lisa M.;Gellman, Samuel H.
我们描述了一个一般的策略，用于创建肽寡聚体，具有非天然的主链，但仍然采取构象非常相似的α-螺旋。这些寡聚体含有α-和β-氨基酸残基（α/β-肽）。如果β含量达到总残基的25-30%，并且β残基沿着主链均匀分布，则通常观察到对蛋白水解降解的显著抗性。这些α/β-肽可以模拟参与蛋白质-蛋白质识别事件的α-螺旋的信息性质，如在许多晶体结构中所记录的。因此，这些非天然寡聚体可以是天然α-螺旋介导的不期望的蛋白质-蛋白质相互作用的拮抗剂的来源，或天然多肽配体是α-螺旋的受体的激动剂的来源。成功包括模拟在促凋亡蛋白中发现的BH 3结构域，这导致抗凋亡Bcl-2家族蛋白的配体，以及模拟gp 41 β结构域，这导致在基于细胞的测定中抑制HIV感染。
We describe a general strategy for creating peptidic oligomers that have unnatural backbones but nevertheless adopt a conformation very similar to the α-helix. These oligomers contain both α- and β-amino acid residues (α/β-peptides). If the β content reaches 25–30% of the residue total, and the β residues are evenly distributed along the backbone, then substantial resistance to proteolytic degradation is often observed. These α/β-peptides can mimic the informational properties of α-helices involved in protein–protein recognition events, as documented in numerous crystal structures. Thus, these unnatural oligomers can be a source of antagonists of undesirable protein–protein interactions that are mediated by natural α-helices, or agonists of receptors for which the natural polypeptide ligands are α-helical. Successes include mimicry of BH3 domains found in proapoptotic proteins, which leads to ligands for anti-apoptotic Bcl-2 family proteins, and mimicry of the gp41 CHR domain, which leads to inhibition of HIV infection in cell-based assays.