Maleimide constrained BAD BH3 domain peptides as BCL-xL Inhibitors: A versatile approach to rapidly identify sites compatible with peptide constraining
Maleimide constrained BAD BH3 domain peptides as BCL-xL Inhibitors: A versatile approach to rapidly identify sites compatible with peptide constraining
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DOI：
10.1016/j.bmcl.2023.129260
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发表时间：
2023-04-03
影响因子：
2.7
通讯作者：
Wilson，Andrew J.
中科院分区：
文献类型：
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作者：
Zhang，Peiyu;Walko，Martin;Wilson，Andrew J.
蛋白质相互作用(PPI)抑制剂的开发仍然是一个主要的挑战。相当多的PPI是由螺旋识别表位介导的；尽管来自此类表位的多肽是有吸引力的抑制剂设计模板，但它们可能不容易采用生物活性构象，对蛋白质分解敏感，很少能诱导最佳的细胞摄取特性。因此，在PPI抑制剂的开发中，抑制多肽已成为一种有效的方法来减轻这些负担。在我们最近报道的通过二溴马来酰亚胺衍生物与两个处于aniandi+4关系的半胱氨酸反应来限制多肽的方法的基础上，在这项研究中，我们展示了该方法的威力，该方法基于来自BAD BH3结构域的19-聚体序列，使用马来酰亚胺-订钉扫描来快速识别理想的限制位置。我们发现，在大多数序列中，马来酰亚胺限制对螺旋度和效价的影响很小或有害，但成功地识别了4个允许马来酰亚胺限制的位置。利用建模和分子动力学(MD)模拟进行的分析表明，由于引入约束，不活跃的受约束多肽可能失去与蛋白质的相互作用。
Development of protein–protein interaction (PPI) inhibitors remains a major challenge. A significant number of PPIs are mediated by helical recognition epitopes; although peptides derived from such epitopes are attractive templates for inhibitor design, they may not readily adopt a bioactive conformation, are susceptible to proteolysis and rarely elicit optimal cell uptake properties. Constraining peptides has therefore emerged as a useful method to mitigate against these liabilities in the development of PPI inhibitors. Building on our recently reported method for constraining peptides by reaction of dibromomaleimide derivatives with two cysteines positioned in aniandi+ 4 relationship, in this study, we showcase the power of the method for rapid identification of ideal constraining positions using a maleimide-staple scan based on a 19-mer sequence derived from the BAD BH3 domain. We found that the maleimide constraint had little or a detrimental impact on helicity and potency in most sequences, but successfully identifiedi,i+ 4 positions where the maleimide constraint was tolerated. Analyses using modelling and molecular dynamics (MD) simulations revealed that the inactive constrained peptides likely lose interactions with the protein as a result of introducing the constraint.