Functionalized peptides incorporating non-canonical ɑ–amino acids: copper(II) coordination and cytotoxic activity

Abstract

Unusual ɑ–amino acids, owing to their ability to accommodate diverse substituents while preserving a chiral center, constitute valuable building blocks in peptidomimetic design. Their incorporation enables fine-tuning of physicochemical and biological properties, while also providing versatile functional handles for further structural modification. Coordination with copper ions represents an additional strategy for modulating peptide activity, often enhancing antimicrobial, antioxidant, and therapeutic potential. In this study, we designed and synthesized two functionalized peptides incorporating selected non-canonical amino acid residues, chosen to improve stability and confer predicted biological activity. We investigated their coordination behavior with Cu(II) ions and evaluated the cytotoxic effects of both peptides and their copper complexes in cancer cell lines and normal fibroblasts. Our results show that Cu(II) coordination markedly increases the in vitro cytotoxic activity of one of the tested compounds. No reduction of viability was detected in normal human dermal fibroblasts within the concentration range tested.