An Original PEG‐Functionalized PS Resin Enables Synthesis of Difficult Peptides: Application to Tirzepatide

Abstract

ABSTRACT Solid‐phase peptide synthesis (SPPS) remains the preferred method for peptide production, but traditional polystyrene (PS)‐based resins often exhibit moderate swelling and aggregation during the synthesis of long or hydrophobic sequences. Polyethylene glycol (PEG)‐modified resins improve solvation but typically suffer from reduced loading capacity. Here, we introduce Seplife Fmoc‐RinkAmide‐PS‐PEG resin, a PEG‐grafted PS support with optimized composition that combines good swelling with higher loading (0.37 mmol g −1 ) compared to a commercial PEG resin (0.27 mmol g −1 ). Its performance was evaluated in the synthesis of several peptides, including pentapeptides, ACP decapeptide, heptapeptide, afamelanotide, and the therapeutic peptide tirzepatide. In all cases, the resin enabled efficient couplings and afforded crude peptides of excellent purity (>95%–98% for small and medium‐size peptides). These results demonstrate that Seplife Fmoc‐RinkAmide‐PS‐PEG‐resin provides a balanced alternative to existing PEG‐based supports, combining high loading and reliable performance, and is particularly suitable for the synthesis of long or complex peptides.