Inhibition of β-catenin/B cell lymphoma 9 protein-protein interaction using α-helix-mimicking sulfono-γ-AApeptide inhibitors
Inhibition of β-catenin/B cell lymphoma 9 protein-protein interaction using α-helix-mimicking sulfono-γ-AApeptide inhibitors
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DOI：
10.1073/pnas.1819663116
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发表时间：
2019-05-28
影响因子：
11.1
通讯作者：
Cai, Jianfeng
中科院分区：
文献类型：
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作者：
Sang, Peng;Zhang, Min;Cai, Jianfeng
模拟α螺旋多肽的合理设计为发现蛋白质-蛋白质相互作用(PPI)的有效抑制剂提供了一种简化的方法。然而，设计穿透细胞的长肽仿制支架，配备与大的蛋白质结合界面相互作用所需的各种官能团，仍然具有挑战性。对于以β-连环蛋白/BCL9 PPI为靶点的情况尤其如此。在这里，我们设计了一系列史无前例的模拟B细胞淋巴瘤9(B cell Lymphoma 9，BCL9)α-螺旋HD2结构域结合模式的螺旋磺化-γ-A多肽。我们的研究表明，磺化-伽马-A肽可以在结构和功能上模拟BCL9的α-螺旋结构域，并选择性地干扰β-连环蛋白/BCL9 PPI，甚至具有更高的效力。更耐人寻味的是，这些磺化-伽马-A肽可以进入癌细胞，与β-连环蛋白结合，破坏β-连环蛋白/BCL9 PPI，并显示出出色的细胞活性，这比BCL9肽要强大得多。此外，我们的酶稳定性研究表明，螺旋磺化-伽马-A肽具有显著的稳定性，在链霉蛋白酶存在下24小时不会降解，从而增强了它们的生物学潜力。这项工作不仅代表了一个模拟α-螺旋并破坏蛋白质-蛋白质相互作用的螺旋磺化-伽马-A肽的例子，也是一个有效的、选择性的和细胞渗透性的非天然叶多肽仿制的极好例子，它破坏了β-连环蛋白/BCL9 PPI。螺旋磺化-γ-A多肽的设计可能导致一种新的策略来调节无数的蛋白质-蛋白质相互作用。
The rational design of alpha-helix-mimicking peptidomimetics provides a streamlined approach to discover potent inhibitors for protein-protein interactions (PPIs). However, designing cell-penetrating long peptidomimetic scaffolds equipped with various functional groups necessary for interacting with large protein-binding interfaces remains challenging. This is particularly true for targeting beta-catenin/BCL9 PPIs. Here we designed a series of unprecedented helical sulfono-gamma-AApeptides that mimic the binding mode of the alpha-helical HD2 domain of B Cell Lymphoma 9 (BCL9). Our studies show that sulfono-gamma-AApeptides can structurally and functionally mimic the alpha-helical domain of BCL9 and selectively disrupt beta-catenin/BCL9 PPIs with even higher potency. More intriguingly, these sulfono-gamma-AApeptides can enter cancer cells, bind with beta-catenin and disrupt beta-catenin/BCL9 PPIs, and exhibit excellent cellular activity, which is much more potent than the BCL9 peptide. Furthermore, our enzymatic stability studies demonstrate the remarkable stability of the helical sulfono-gamma-AApeptides, with no degradation in the presence of pronase for 24 h, augmenting their biological potential. This work represents not only an example of helical sulfono-gamma-AApeptides that mimic alpha-helix and disrupt protein-protein interactions, but also an excellent example of potent, selective, and cell-permeable unnatural foldameric peptidomimetics that disrupt the beta-catenin/BCL9 PPI. The design of helical sulfono-gamma-AApeptides may lead to a new strategy to modulate a myriad of protein-protein interactions.