A versatile “Synthesis Tag” (SynTag) for the chemical synthesis of aggregating peptides and proteins

20 September 2023, Version 2
This content is a preprint and has not undergone peer review at the time of posting.


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 via a cleavable MeDbz linker. “SynTag” effectively improves batch- and flow-SPPS of “difficult sequences”, enhances 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.


Chemical Protein Synthesis
Solid-Phase Peptide Synthesis
Difficult Sequences
Protein Tag

Supplementary materials

Supporting Information
Experimental procedures and analytical data.


Comments are not moderated before they are posted, but they can be removed by the site moderators if they are found to be in contravention of our Commenting Policy [opens in a new tab] - please read this policy before you post. Comments should be used for scholarly discussion of the content in question. You can find more information about how to use the commenting feature here [opens in a new tab] .
This site is protected by reCAPTCHA and the Google Privacy Policy [opens in a new tab] and Terms of Service [opens in a new tab] apply.