Cu chelation in biological systems is of interest as a tool to study the metabolism of this essential metal or for applications in the case of diseases with a systemic or local Cu overload, such as Wilson’s or Alzheimer’s disease. The choice of the chelating agent must meet several criteria. Among others, affinities and kinetics of metal binding and related metal selectivity are important parameters of the chelators to consider. Here, we report on the synthesis and characterization of Cu-binding properties of two ligands, L1 and L2, derivatives of the well-known peptidic Cu^II-binding motif Xxx-Zzz-His (also called ATCUN), where Cu^II is bound to the N-terminal amine, two amidates, and the imidazole. In either L, the N-terminal amine was replaced with a pyridine, and for L2, one amide was replaced with an amine compared to Xxx-Zzz-His. In particular, L2 showed several interesting features, including a Cu^II-binding affinity with a log K_D^app = −16.0 similar to that of EDTA and stronger than all reported ATCUN peptides. L2 showed high selectivity for Cu^II over Zn^II and other essential metal ions, even under the challenging conditions of the presence of human serum albumin. Further, L2 showed fast and efficient Cu^II redox silencing qualities and Cu^II-L2 was stable in the presence of mM GSH concentrations. Benefitting the fact that L2 can be easily elongated on its peptide part by standard SPPS to add other functions, L2 has attractive properties as a Cu^II chelator for application in biological systems.

中文翻译：

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在保持高选择性和快速氧化还原沉默的情况下，将肽 Xxx-Zzz-His 基序衍生为具有 Attomolar CuII 亲和力的配体

生物系统中的铜螯合作为研究这种必需金属代谢的工具或在全身或局部铜超载疾病（如威尔逊氏病或阿尔茨海默氏病）中的应用引起了人们的兴趣。螯合剂的选择必须满足几个标准。其中，金属结合的亲和力和动力学以及相关的金属选择性是螯合剂要考虑的重要参数。在这里，我们报告了两个配体 L1 和 L2 的铜结合特性的合成和表征，它们是著名的肽 Cu ^II结合基序 Xxx-Zzz-His（也称为 ATCUN）的衍生物，其中 Cu ^II与 N-末端胺、两个酰胺化物和咪唑结合。与 Xxx-Zzz-His 相比，在任一 L 中，N-末端胺被吡啶取代，对于 L2，一个酰胺被胺取代。特别是，L2 显示出几个有趣的特征，包括与 log  K _D ^app = -16.0 的Cu ^II结合亲和力，类似于 EDTA 并且比所有报道的 ATCUN 肽都强。L2 对 Cu ^II的选择性高于 Zn ^II和其他必需金属离子，即使在人血清白蛋白存在的挑战性条件下也是如此。此外，L2 显示出快速有效的 Cu ^II氧化还原沉默特性，而 Cu ^II-L2 在 mM GSH 浓度存在下是稳定的。受益于 L2 可以通过标准 SPPS 轻松延长其肽部分以添加其他功能这一事实，L2 作为 Cu ^II螯合剂在生物系统中的应用具有吸引人的特性。