The precise pairing of cysteine (Cys) residues is essential for the conformational folding and stabilization of many proteins and natural disulfide-rich peptides. In natural systems, precise disulfide pairing is achieved by multiple oxidation, reduction, and rearrangement steps, which is predetermined by the primary sequence of the polypeptide chains and strategically regulated by molecular chaperones and enzymes such as protein disulfide isomerase. These requisites, however, are notoriously difficult to be reconstitutedin vitrofor the synthesis of disulfide-rich/multicyclic peptides, particularly when the primary sequence has to be extensively manipulated for the development of peptide therapeutics and ligands. Thus, we are particularly interested in developing novel disulfide pairing strategies to direct the folding of peptides without protecting groups, extensive manipulation of primary sequence, and resourse to elaborate post-synthetic reactions. Our work would enable the development of novel disulfide-rich scaffolds for the design of structurally-constrained peptide ligands and drugs.
