Probing the structural requirements of peptoids that inhibit HDM2-p53 interactions
Probing the structural requirements of peptoids that inhibit HDM2-p53 interactions
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DOI：
10.1021/ja056344c
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发表时间：
2006-02-15
影响因子：
15
通讯作者：
Appella, DH
中科院分区：
文献类型：
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作者：
Hara, T;Durell, SR;Appella, DH
许多细胞过程是由蛋白质-蛋白质相互作用控制的，选择性抑制这些相互作用可能导致几种疾病的新疗法的发展。在癌症领域，与p53蛋白结合并使其失活的人类双分钟2 （HDM2）蛋白的过度表达与肿瘤侵袭性和耐药性有关。总的来说，抑制蛋白质与合成分子的相互作用是具有挑战性的，目前在药物开发中仍然是一个很大程度上未知的领域。制造蛋白质-蛋白质相互作用抑制剂的一种策略是，利用一种非天然支架作为侧链的附着点，重建参与蛋白质与另一蛋白质结合的侧链的三维排列。在这项研究中，我们使用寡聚肽作为支架，开始开发一种总体策略，在这种策略中，我们可以合理地设计可以优化抑制蛋白质-蛋白质相互作用的合成分子。我们利用HDM2-p53复合物的结构信息来设计我们的第一类肽类抑制剂，我们在这里详细介绍了用适当的侧链修饰肽类的策略，这些侧链是HDM2-p53结合的有效抑制剂。虽然我们最初试图开发刚性的螺旋类肽作为HDM2结合剂，但令人惊讶的是，最好的抑制剂是缺乏任何螺旋促进基团的类肽。这些结果表明，从刚性肽类支架开始开发新的抑制剂可能并不总是最佳的。
Many cellular processes are controlled by protein-protein interactions, and selective inhibition of these interactions could lead to the development of new therapies for several diseases. In the area of cancer, overexpression of the protein, human double minute 2 (HDM2), which binds to and inactivates the protein p53, has been linked to tumor aggressiveness and drug resistance. In general, inhibition of protein-protein interactions with synthetic molecules is challenging and currently remains a largely uncharted area for drug development. One strategy to create inhibitors of protein-protein interactions is to recreate the three-dimensional arrangement of side chains that are involved in the binding of one protein to another, using a nonnatural scaffold as the attachment point for the side chains. In this study, we used oligomeric peptoids as the scaffold to begin to develop a general strategy in which we could rationally design synthetic molecules that can be optimized for inhibition of protein-protein interactions. Structural information on the HDM2-p53 complex was used to design our first class of peptoid inhibitors, and we provide here, in detail, the strategy to modify peptoids with the appropriate side chains that are effective inhibitors of HDM2-p53 binding. While we initially tried to develop rigid, helical peptoids as HDM2 binders, the best inhibitors were surprisingly peptoids that lacked any helix-promoting groups. These results indicate that starting with rigid peptoid scaffolds may not always be optimal to develop new inhibitors.