Structure-function relationship within helical peptoids for Cu²⁺ chelation in the context of Alzheimer's disease

Peptoids (N-substituted glycine oligomers) represent an excellent platform for drug development, such as selective chelators for Cu²⁺ ions towards chelation therapy, due to their efficient synthesis, high stability and good bioavailability. We previously showed that peptoids helicity is essential for selective Cu²⁺ binding and identified a unique peptoid hexamer, having 2,2':6',2″-terpyridine, and 8-hydroxyquinoline as metal-binding sidechains facing the same side of the helix, which exhibits high selectivity to Cu²⁺ ions. However, maintaining a stable helix required the incorporation of bulky chiral sidechains, resulting in a hydrophobic peptoid, insoluble in aqueous solutions, and limited in its use as a drug candidate. Our attempts to solubilize this peptoid led to the discovery of a water-soluble sequence able to selectively extract Cu²⁺ from Cu-amyloid complex, and by this stop the formation of reactive oxygen species (ROS) in the context of Alzheimer's disease (AD). This peptoid, however, had limited solubility in buffer solutions (that mimic biological environment), thus its potential for further development as a therapeutic for AD was limited. In this current study, we explore the structure-function relationship within a newly synthesized set of helical and water-soluble peptoids. By extensive spectroscopic analysis we test the effect of helix stability as well as the type and number of the solubilizing group(s) and their position along the sequence, on the solubility of these peptoids in buffer, and on their selectivity for Cu and ability to inhibit ROS production. The results provide insights about the relationships between the structure of the peptoids/Cu-peptoids and ROS production inhibition.