Autor: |
Zhang Q; Department of Chemistry, Brandeis University, 415 South Street, Waltham, Massachusetts 02453, United States., Tan W; Department of Chemistry, Brandeis University, 415 South Street, Waltham, Massachusetts 02453, United States., Liu Z; Department of Chemistry, Brandeis University, 415 South Street, Waltham, Massachusetts 02453, United States., Zhang Y; Department of Chemistry, Brandeis University, 415 South Street, Waltham, Massachusetts 02453, United States., Wei WS; Martin A. Fisher School of Physics, Brandeis University, 415 South Street, Waltham, Massachusetts 02453, United States., Fraden S; Martin A. Fisher School of Physics, Brandeis University, 415 South Street, Waltham, Massachusetts 02453, United States., Xu B; Department of Chemistry, Brandeis University, 415 South Street, Waltham, Massachusetts 02453, United States. |
Abstrakt: |
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. |