Cancer and other disease states can change the landscape of proteins post-translationally tagged with ubiquitin (Ub) chains. Molecules capable of modulating the functions of Ub chains are potential therapeutic agents, but their discovery represents a significant challenge. Recently, it was shown that de novo cyclic peptides, selected from trillion-member random libraries, are capable of binding particular Ub chains. However, these peptides were overwhelmingly proteinogenic, so the prospect of in vivo activity was uncertain. Here, we report the discovery of small, non-proteinogenic cyclic peptides, rich in non-canonical features like N-methylation, which can tightly bind Lys48-linked Ub chains. These peptides engage three Lys48-linked Ub units simultaneously, block the action of deubiquitinases and the proteasome, induce apoptosis in vitro, and attenuate tumor growth in vivo. This highlights the potential of non-proteinogenic cyclic peptide screening to rapidly find in vivo-active leads, and the targeting of ubiquitin chains as a promising anti-cancer mechanism of action.

中文翻译：

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N-甲基化非蛋白环肽对泛素链的体内调节

癌症和其他疾病状态可以改变翻译后标记有泛素 (Ub) 链的蛋白质的格局。能够调节 Ub 链功能的分子是潜在的治疗剂，但它们的发现是一项重大挑战。最近，表明从万亿成员随机库中选择的从头环肽能够结合特定的 Ub 链。然而，这些肽绝大多数是蛋白质原性的，因此体内活性的前景是不确定的。在这里，我们报告发现了小的、非蛋白原性环肽，富含非规范特征，如N-甲基化，可以紧密结合 Lys48 连接的 Ub 链。这些肽同时与三个 Lys48 连接的 Ub 单元结合，阻断去泛素化酶和蛋白酶体的作用，在体外诱导细胞凋亡，并在体内减弱肿瘤生长。这突出了非蛋白原性环肽筛选快速发现体内活性先导物的潜力，以及靶向泛素链作为一种有前景的抗癌作用机制。