Templated native chemical ligation: peptide chemistry beyond protein synthesis

Native chemical ligation (NCL) is a powerful method for the convergent synthesis of proteins and peptides. In its original format, NCL between a peptide containing a C-terminal thioester and another peptide offering an N-terminal cysteine has been used to enable protein synthesis of unprotected peptide fragments. However, the applications of NCL extend beyond the scope of protein synthesis. For instance, NCL can be put under the control of template molecules. In such a scenario, NCL enables the design of conditional reaction systems in which, peptide bond formation occurs only when a specific third party molecule is present. In this review, we will show how templates can be used to control the reactivity and chemoselectivity of NCL reactions. We highlight peptide and nucleic-acid-templated NCL reactions and discuss potential applications in nucleic acid diagnosis, origin-of-life studies and gene-expression-specific therapies.