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Enzymatic Assemblies of Thiophosphopeptides Instantly Target Golgi Apparatus and Selectively Kill Cancer Cells **
Author(s) -
Tan Weiyi,
Zhang Qiuxin,
Wang Jiaqing,
Yi Meihui,
He Hongjian,
Xu Bing
Publication year - 2021
Publication title -
angewandte chemie
Language(s) - English
Resource type - Journals
eISSN - 1521-3757
pISSN - 0044-8249
DOI - 10.1002/ange.202102601
Subject(s) - dephosphorylation , golgi apparatus , chemistry , phosphopeptide , endocytosis , cancer cell , endosome , phosphodiester bond , cysteamine , biochemistry , enzyme , alkaline phosphatase , biophysics , phosphatase , phosphorylation , biology , cancer , intracellular , cell , rna , genetics , gene
Changing an oxygen atom of the phosphoester bond in phosphopeptides by a sulfur atom enables instantly targeting Golgi apparatus (GA) and selectively killing cancer cells by enzymatic self‐assembly. Specifically, conjugating cysteamine S‐phosphate to the C‐terminal of a self‐assembling peptide generates a thiophosphopeptide. Being a substrate of alkaline phosphatase (ALP), the thiophosphopeptide undergoes rapid ALP‐catalyzed dephosphorylation to form a thiopeptide that self‐assembles. The thiophosphopeptide enters cells via caveolin‐mediated endocytosis and macropinocytosis and instantly accumulates in GA because of dephosphorylation and formation of disulfide bonds in Golgi by themselves and with Golgi proteins. Moreover, the thiophosphopeptide potently and selectively inhibits cancer cells (HeLa) with the IC 50 (about 3 μM), which is an order of magnitude more potent than that of the parent phosphopeptide.