Opportunities and challenges in the synthesis of thioamidated peptides

Abstract

Chemical modifications of peptides hold great promise for modulating their pharmacological properties. In the last few decades amide to thioamide substitution has been widely explored to modulate the conformation, non-covalent interactions, and proteolytic stability of peptides. Despite widespread utilization, there are some potential limitations including epimerization and degradation under basic and acidic conditions, respectively. In this chapter, we present the synthetic method to build thio-precursors, their site-specific incorporation onto a growing peptide chain, and troubleshooting during the elongation of thioamidated peptides. This highly efficient, rapid, and robust method can be used for positional scanning of the thioamide bond.

Keywords: Lawesson's reagent; Metabolic stability; Solid-phase-peptide-synthesis; Thioamide; Thionation; Thiopeptide.