Installation of Metal-Binding Functionality at Lysine Residues via Azide-Alkyne "Click Chemistry"

Abstract

A novel non-natural amino acid designed to bind divalent metal ions, dubbed Lys(PYRIT), was prepared in a “click reaction” by treating Fmoc-Lys(N3)-OH with 2-ethynylpyridine and Cu(I). It was incorporated into a 12-residue peptide using standard Fmoc solid phase synthesis protocols. Multiple spectroscopic techniques (NMR, ESI-QToF-MS, UV-vis, and CD) confirm that the PYRIdinyl/Triazolyl side-chain binds Zn(II) and Cu(II) in the presence of competing natural residues such as histidine and glutamic acid. It remains unclear whether metal ions mediate the oligomerization of the Y2K PYRIT peptide, as is believed to be important in neurodegenerative diseases.