Stabilization of Aliphatic Phosphines by Auxiliary Phosphine Sulfides Offers Zeptomolar Affinity and Unprecedented Selectivity for Probing Biological CuI

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.