Department of Chemistry, Brandeis University, 415 South Street, Waltham, Massachusetts 02453, United States.
Martin A. Fisher School of Physics, Brandeis University, 415 South Street, Waltham, Massachusetts 02453, United States.
J Am Chem Soc. 2024 May 15;146(19):12901-12906. doi: 10.1021/jacs.4c03101. Epub 2024 May 3.
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 () assemblies capable of depleting cholesterol and inhibiting cancer cells. Peptide 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 depletes cell membrane cholesterol. It localizes in membrane-rich organelles, including the endoplasmic reticulum, Golgi apparatus, and lysosomes. Furthermore, 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.
富含胆固醇的膜在癌症的发生和发展中起着关键作用，因此需要创新的方法来靶向这些膜以抑制癌症。在这里，我们报告了第一个能够消耗胆固醇和抑制癌细胞的非天然肽（）组装体的案例。肽自组装成胶束，并被癌细胞迅速吸收，尤其是与急性胆固醇耗竭剂（MβCD）结合时。点击化学已证实，消耗细胞膜胆固醇。它定位于富含膜的细胞器中，包括内质网、高尔基体和溶酶体。此外，它能够有效抑制恶性癌细胞，与降胆固醇药物协同作用。对照实验证实，C 端封端和非天然氨基酸残基（即 BiP）对于胆固醇耗竭和有效抑制癌细胞都是必不可少的。这项工作强调了非天然肽组装体作为一种有前途的平台，可用于控制细胞膜以控制细胞命运。
