Full elucidation of the functions and homeostatic pathways of biological copper requires tools that can selectively recognize and manipulate this trace nutrient within living cells and tissues, where it exists primarily as Cu^I. Buffered at attomolar concentrations, intracellular Cu^I is, however, not readily accessible to commonly employed amine and thioether‐based chelators. Herein, we reveal a chelator design strategy in which phosphine sulfides aid in Cu^I coordination while simultaneously stabilizing aliphatic phosphine donors, producing a charge‐neutral ligand with low‐zeptomolar dissociation constant and 10¹⁷‐fold selectivity for Cu^I over Zn^II, Fe^II, and Mn^II. As illustrated by reversing ATP7A trafficking in cells and blocking long‐term potentiation of neurons in mouse hippocampal brain tissue, the ligand is capable of intercepting copper‐dependent processes. The phosphine sulfide‐stabilized phosphine (PSP) design approach, which confers resistance towards protonation, dioxygen, and disulfides, could be readily expanded towards ligands and probes with tailored properties for exploring Cu^I in a broad range of biological systems.

中文翻译：

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辅助膦硫化物对脂肪族膦的稳定作用提供了Zeptomolar亲和力和前所未有的选择性来探测生物CuI。

要充分阐明生物铜的功能和体内平衡途径，就需要能够选择性识别和操纵活细胞和组织（主要以Cu ^I形式存在）中的微量养分的工具。缓冲在attomolar浓度，细胞内的Cu^我是，然而，不容易接近到通常使用的胺和硫醚系螯合剂。在这里，我们揭示了一种螯合剂设计策略，其中磷化氢硫化物有助于Cu ^I的配位，同时稳定脂肪族膦的供体，产生具有低原子化解离常数的电荷中性配体，对Cu ^I的选择性比Zn ^II和Fe高10 ¹⁷倍。^II和Mn ^II。如通过逆转细胞中ATP7A的运输和阻断小鼠海马脑组织中神经元的长期增强所说明的，该配体能够拦截铜依赖性过程。硫化膦稳定化的膦（PSP）的设计方法，其赋予对质子化，分子氧，和二硫化物性，可以向配体和探针可以容易地扩展以探索铜特制性能^我在宽范围的生物系统。