Enhancing native chemical ligation for challenging chemical protein syntheses

Abstract

Native chemical ligation has enabled the chemical synthesis of proteins for a wide variety of applications (e.g., mirror-image proteins). However, inefficiencies of this chemoselective ligation in the context of large or otherwise challenging protein targets can limit the practical scope of chemical protein synthesis. In this review, we focus on recent developments aimed at enhancing and expanding native chemical ligation for challenging protein syntheses. Chemical auxiliaries, use of selenium chemistry, and templating all enable ligations at otherwise suboptimal junctions. The continuing development of these tools is making the chemical synthesis of large proteins increasingly accessible.

Keywords: Auxiliary-mediated ligation; Chemical protein synthesis; Diselenide-selenoester ligation; Mirror-image proteins; Native chemical ligation; Peptide ligation; Selenocysteine; Solid-phase peptide synthesis; Templated ligation; Traceless templated ligation.