Protein structures frequently contain repetitive peptidic motifs that are known to be associated with important physical or biological functions. One appealing synthetic strategy for producing repetitive peptidic motifs is to oligomerize chemoselectively unprotected bifunctional peptidic monomers in water. Unfortunately, this approach is confronted with the competitive irreversible cyclization of the bifunctional monomer, resulting in dramatically low degrees of polymerization.

We undertook the challenge of addressing this issue by utilizing the native chemical ligation (NCL), chosen for its mild reaction conditions, ease of implementation, and ongoing dynamic development. As expected, the use of a bifunctional peptide monomer equipped with an N-terminal cysteine (Cys) residue and a C-terminal thioester group failed to produce the target oligomer due to the massive cyclization of the monomer. In contrast, appending a selenoethyl arm to the a-amino group of Cys led to monomer oligomerization, producing native peptide junctions to cysteine (Figure A). Key to this finding is the reversibility of monomer cyclization, which is no longer a dead end as for classical NCL with Cys residue (Figure B). Another important feature of N-selenoethyl cysteine (SetCys) is the spontaneous loss of its selenoethyl arm to produce a native Cys residue in situ (Figure C).