A Versatile "Synthesis Tag" (SynTag) for the Chemical Synthesis of Aggregating Peptides and Proteins

Solid-phase peptide synthesis (SPPS) and native chemical ligation (NCL) are powerful methods for obtaining peptides and proteins that are otherwise inaccessible. Nonetheless, numerous sequences are difficult to prepare via SPPS, and cleaved peptides often have low aqueous solubility. To address these challenges, we developed a "Synthesis Tag" consisting of six arginines connected to the target sequence via a cleavable MeDbz linker. "SynTag" effectively improves batch- and flow-SPPS of "difficult sequences", enhances the solubility of the cleaved peptides, and provides direct access to native sequences by hydrolysis, or peptide thioesters for NCL. We demonstrate its utility in the first chemical synthesis of the MYC transactivation domain with a single NCL. We envisage SynTag to become a broadly applicable tool that enables the synthesis and study of previously unattainable peptides and proteins.