Derivatization of the Peptidic Xxx-Zzz-His Motif toward a Ligand with Attomolar CuII Affinity under Maintaining High Selectivity and Fast Redox Silencing

Twonew Cu-II-ligand complexes (Cu-II-L1 and Cu-II-L2) inspired by the well-known N-terminalpeptidic motif Xxx-Zzz-His, also called the ATCUN motif, are reported.The replacement of the amine and amidate by a pyridine and an amine,respectively, increased substantially the Cu-II affinityof L2 up to the range of EDTA. At the same time, Cu-II-L2also kept several properties of the parent ATCUN motif, in particularthe high selectivity for Cu-II and the redox silencing ofCu(II) in this complex. Cu chelation in biological systemsis of interest asa tool tostudy the metabolism of this essential metal or for applications inthe case of diseases with a systemic or local Cu overload, such asWilson's or Alzheimer's disease. The choice of the chelatingagent must meet several criteria. Among others, affinities and kineticsof metal binding and related metal selectivity are important parametersof the chelators to consider. Here, we report on the synthesis andcharacterization of Cu-binding properties of two ligands, L1 and L2,derivatives of the well-known peptidic Cu-II-binding motifXxx-Zzz-His (also called ATCUN), where Cu-II is bound tothe N-terminal amine, two amidates, and the imidazole. In either L,the N-terminal amine was replaced with a pyridine, and for L2, oneamide 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 strongerthan all reported ATCUN peptides. L2 showed high selectivity for Cu-II over Zn-II and other essential metal ions, evenunder the challenging conditions of the presence of human serum albumin.Further, L2 showed fast and efficient Cu-II redox silencingqualities and Cu-II-L2 was stable in the presence of mMGSH concentrations. Benefitting the fact that L2 can be easily elongatedon its peptide part by standard SPPS to add other functions, L2 hasattractive properties as a Cu-II chelator for applicationin biological systems.