Cholesterol-rich membranes play a pivotal role in cancer initiation and progression, necessitating innovative approaches to target these membranes for cancer inhibition. Here we report the first case of unnatural peptide (1) assemblies capable of depleting cholesterol and inhibiting cancer cells. Peptide 1 self-assembles into micelles and is rapidly taken up by cancer cells, especially when combined with an acute cholesterol-depleting agent (MβCD). Click chemistry has confirmed that 1 depletes cell membrane cholesterol. It localizes in membrane-rich organelles, including the endoplasmic reticulum, Golgi apparatus, and lysosomes. Furthermore, 1 potently inhibits malignant cancer cells, working synergistically with cholesterol-lowering agents. Control experiments have confirmed that C-terminal capping and unnatural amino acid residues (i.e., BiP) are essential for both cholesterol depletion and potent cancer cell inhibition. This work highlights unnatural peptide assemblies as a promising platform for targeting the cell membrane in controlling cell fates.

中文翻译：

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非天然肽组装体可快速消耗胆固醇并有效抑制癌细胞


富含胆固醇的膜在癌症的发生和进展中发挥着关键作用，因此需要创新的方法来靶向这些膜以抑制癌症。在这里，我们报告了首例能够消耗胆固醇并抑制癌细胞的非天然肽（1）组装体。肽 1 自组装成胶束并迅速被癌细胞吸收，尤其是与急性胆固醇消耗剂 (MβCD) 结合使用时。点击化学已证实 1 会消耗细胞膜胆固醇。它定位于富含膜的细胞器，包括内质网、高尔基体和溶酶体。此外，1 与降胆固醇药物协同作用，可有效抑制恶性癌细胞。对照实验已证实 C 末端加帽和非天然氨基酸残基（即 BiP）对于胆固醇消耗和有效抑制癌细胞至关重要。这项工作强调非天然肽组装体作为靶向细胞膜控制细胞命运的有前途的平台。