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

Area of Science:

• Medicinal Chemistry
• Biochemistry
• Materials Science

Background:

• Synthetic molecules for chelating copper ions (Cu²⁺) are explored for treating diseases like Wilson disease and cancer.
• Peptoids, N-substituted glycine oligomers, offer advantages as synthetic chelators due to their peptide-like structure and tunable sequences.

Purpose of the Study:

• To investigate the influence of non-coordinating side chains on the selectivity of peptoid chelators for Cu²⁺ in aqueous media.
• To understand the structural factors governing Cu²⁺ chelation selectivity in synthetic peptoid molecules.

Main Methods:

• Synthesis of peptoid trimers with varied non-coordinating side chains (aromatic, aliphatic, chiral, non-chiral) at the C-terminus.
• Systematic variation of the non-coordinating group's position within the peptoid sequence.
• Spectroscopic analysis to evaluate Cu²⁺ chelation and selectivity.

Main Results:

• The nature and position of the non-coordinating side chain significantly impact peptoid selectivity for Cu²⁺.
• Peptoids featuring bulky chiral groups at the C-terminus demonstrated high selectivity for Cu²⁺.
• A selective peptoid chelator successfully removed Cu²⁺ from metallothionein in a HEPES buffer.

Conclusions:

• Peptoid sequence engineering, specifically the incorporation of bulky chiral groups, is a viable strategy for developing selective Cu²⁺ chelators.
• These findings support the therapeutic potential of tailored peptoids for managing copper-related disorders and in biochemical applications.