Aib-based peptide backbone as scaffolds for helical peptide mimics
Aib-based peptide backbone as scaffolds for helical peptide mimics
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DOI：
10.1034/j.1399-3011.2002.201005.x
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发表时间：
2002-08-01
期刊：
影响因子：
--
通讯作者：
Roy, S
中科院分区：
文献类型：
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作者：
Banerjee, R;Basu, G;Roy, S
可以干预和破坏治疗上重要的蛋白质-蛋白质相互作用的螺旋肽是有吸引力的药物靶点。为了制定开发此类螺旋肽模拟物的通用策略，我们研究了将α-氨基异丁酸（Aib）（一种对螺旋骨架具有强烈偏好的氨基酸）作为设计肽中唯一的螺旋启动子的效果。具体来说，我们关注 hdm2-p53 相互作用，它对于多种癌症的发展至关重要。对应于 p53 的 hdm2 相互作用部分的肽，在结合状态下呈螺旋状，但在溶液中缺乏结构，作为肽设计的起点，涉及用 Aib 替换非相互作用残基。通过核磁共振和圆二色性判断，Aib 的掺入在保留相互作用残基的同时，导致螺旋结构显着增加，特别是在 C 末端区域。与 hdm2 的相互作用也被发现增强。最有趣的是，发现胰蛋白酶的裂解被延迟了几个数量级。我们的结论是，掺入 Aib 是创建具有增强的受体结合和较低的蛋白酶裂解率的肽螺旋模拟物的可行策略。
Helical peptides that can intervene and disrupt therapeutically important protein-protein interactions are attractive drug targets. In order to develop a general strategy for developing such helical peptide mimics, we have studied the effect of incorporating a-amino isobutyric acid (Aib), an amino acid with strong preference for helical backbone, as the sole helix promoter in designed peptides. Specifically, we focus on the hdm2-p53 interaction, which is central to development of many types of cancer. The peptide corresponding to the hdm2 interacting part of p53, helical in bound state but devoid of structure in solution, served as the starting point for peptide design that involved replacement of noninteracting residues by Aib. Incorporation of Aib, while preserving the interacting residues, led to significant increase in helical structure, particularly at the C-terminal region as judged by nuclear magnetic resonance and circular dichroism. The interaction with hdm2 was also found to be enhanced. Most interestingly, trypsin cleavage was found to be retarded by several orders of magnitude. We conclude that incorporation of Aib is a feasible strategy to create peptide helical mimics with enhanced receptor binding and lower protease cleavage rate.