Sequence-function relationship within water-soluble Peptoid Chelators for Cu2.

Chelation of Cu2+ by synthetic molecules is an emerging therapeutic approach for treating several illnesses in human body such as Wilson disease, cancer and more. Among synthetic metal chelators, those based on peptoids - N-substituted glycine oligomers - are advantageous due to their structural similarity to peptides, ease of synthesis on solid support and versatile controlled sequences. Tuning peptoid sequences, via systematically changing at least one side chain, can facilitate and control their function. Along these lines, this work aims to explore the role of the non-coordinating side chain within peptoid chelators in order to understand the factors that control the selectivity of these chelators to Cu2+ in water medium. To this aim, a set of peptoid trimers having a pyridine group at the acetylated N-terminal, a 2,2'-bipyridine group at the second position and a non-coordinating group at the C-terminus, where the latter is systematically varied between aromatic, aliphatic, chiral or non-chiral, were investigated as selective chelators for Cu2+. The effect of the position of the non-coordinating group on the selectivity of the peptoid to Cu2+ was also tested. Based on extensive spectroscopic data, we found that the choice of the non-coordinating group along with its position dramatically influences the selectivity of the peptoids to Cu2+. We showed that peptoids having bulky chiral groups at the C-terminus enable high selectivity to Cu2+. We further demonstrated the ability of one of the selective chelators to remove Cu2+ from the natural copper binding protein metallothionein in HEPES (4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid) buffer medium.