Peptides on Tap: Automated Flow Synthesis With Standard HPLC

Article Article scientifique Article Peptides on Tap: Automated Flow Synthesis With Standard HPLC eng 2026-08-09 author Romanens Patrick Department of Organic Chemistry Faculty of Sciences University of Geneva Geneva Switzerland 22629 Département de chimie organique (CHIOR) author Barluenga Badiola Sofia 0000-0003-3830-1178 Department of Organic Chemistry Faculty of Sciences University of Geneva Geneva Switzerland 810177 Département de chimie organique (CHIOR) author Dockerill Millicent Department of Organic Chemistry Faculty of Sciences University of Geneva Geneva Switzerland 949778 Chimie organique (groupe 5) (CHOR5) author Zhao Guixian Department of Organic Chemistry Faculty of Sciences University of Geneva Geneva Switzerland 419304 Département de chimie organique (CHIOR) author Russo Francesco Department of Organic Chemistry Faculty of Sciences University of Geneva Geneva Switzerland 956582 Chimie organique (groupe 5) (CHOR5) author Winssinger Nicolas 0000-0003-1636-7766 Department of Organic Chemistry Faculty of Sciences University of Geneva Geneva Switzerland 769664 Département de chimie organique (CHIOR) e70091 10.1002/hlca.70091 0018-019X https://onlinelibrary.wiley.com/doi/10.1002/hlca.70091 <p>Peptide synthesis is central to biomedical research, yet automated flow synthesis typically requires custom‐built instrumentation, limiting accessibility beyond specialized laboratories. Here we demonstrate that a standard analytical HPLC can be repurposed for fully automated flow‐based peptide synthesis. By packing a short guard column with resin and programming reagent injections through the autosampler, we achieved efficient coupling and deprotection cycles under temperature‐controlled flow, using TBEC/Oxyma activation. This setup exploits the precise flow control, heating, and in‐line UV detection intrinsic to HPLC systems, enabling real‐time monitoring of Fmoc deprotection. Using this approach, we synthesized peptides up to 30 residues, including GLP‐1 and bivalirudin, with comparable yields and purity to conventional solid‐phase synthesis. No significant epimerization was observed under optimized conditions, and crude bivalirudin displayed thrombin inhibition activity identical to purified reference material. The method was also used to obtain a 58‐residue miniprotein in under 7 h on mg scale. This work introduces a simple, safe, and economical platform for automated peptide synthesis with the advent of high temperature flow accessible to any laboratory equipped with an HPLC.</p> Dewey 540 Swiss National Science Foundation 36 Département de chimie organique 141 false 762 Groupe Winssinger Helvetica chimica acta b473515b-2654-405e-ba54-e08bb680689d Article (Published version) Public 210x-PeptideOnTap.pdf 2669745 application/pdf CC BY-4.0 3a0505b923534c28f721bc852e1b367fb73438e6410298d808d250b219714237 openAccess Faculté des sciences / Section de chimie et biochimie / Département de chimie organique

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