De novo macrocyclic peptides that specifically modulate Lys48-linked ubiquitin chains
De novo macrocyclic peptides that specifically modulate Lys48-linked ubiquitin chains
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DOI：
10.1038/s41557-019-0278-x
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发表时间：
2019-07-01
期刊：
影响因子：
21.8
通讯作者：
Brik, Ashraf
中科院分区：
文献类型：
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作者：
Nawatha, Mickal;Rogers, Joseph M.;Brik, Ashraf
在癌症治疗中有希望的方法是找到直接结合泛素（Ub）链的配体。然而，鉴于Ub聚合物长度和连接的范围及其微妙的结构差异，寻找能够紧密和特异性结合Ub链的分子具有挑战性。在这里，我们使用全化学合成的蛋白质，以产生高度均匀的Ub链的筛选对万亿成员的大环肽库（RaPID系统）。通过NMR研究证实，发现从头环肽可以紧密且特异性地结合K48连接的Ub链。这些环肽保护K48连接的Ub链不受去泛素化酶的影响，并防止Ub标记蛋白的蛋白酶体降解。环肽可以进入细胞，抑制生长并诱导程序性细胞死亡，为治疗干预开辟了新的机会。这种高度合成的方法，同时在体外进行蛋白质靶点生成和环肽发现，将使其他精心设计的翻译后修饰靶点可用于药物发现。
A promising approach in cancer therapy is to find ligands that directly bind ubiquitin (Ub) chains. However, finding molecules capable of tightly and specifically binding Ub chains is challenging given the range of Ub polymer lengths and linkages and their subtle structural differences. Here, we use total chemical synthesis of proteins to generate highly homogeneous Ub chains for screening against trillion-member macrocyclic peptide libraries (RaPID system). De novo cyclic peptides were found that can bind tightly and specifically to K48-linked Ub chains, confirmed by NMR studies. These cyclic peptides protected K48-linked Ub chains from deubiquitinating enzymes and prevented proteasomal degradation of Ub-tagged proteins. The cyclic peptides could enter cells, inhibit growth and induce programmed cell death, opening new opportunities for therapeutic intervention. This highly synthetic approach, with both protein target generation and cyclic peptide discovery performed in vitro, will make other elaborate post-translationally modified targets accessible for drug discovery.