Sequence–Activity Relationship of ATCUN Peptides in the Context of Alzheimer’s Disease

Amino-terminal Cu(II) and Ni(II) (ATCUN) binding sequences are widespread in the biological world. Here, we report on the study of eight ATCUN peptides aimed at targeting copper ions and stopping the associated formation of reactive oxygen species (ROS). This study was actually more focused on Cu(Aβ)-induced ROS production in which the Aβ peptide is the “villain” linked to Alzheimer’s disease. The full characterization of Cu(II) binding to the ATCUN peptides, the Cu(II) extraction from Cu(II)(Aβ), and the ability of the peptides to prevent and/or stop ROS formation are described in the relevant biological conditions. We highlighted in this research that all the ATCUN motifs studied formed the same thermodynamic complex but that the addition of a second histidine in position 1 or 2 allowed for an improvement in the Cu(II) uptake kinetics. This kinetic rate was directly related to the ability of the peptide to stop the Cu(II)(Aβ)-induced production of ROS, with the most efficient motifs being HWHG and HGHW.