Nature-Inspired Continuous N-C Chain Elongation Enables Sustainable Peptide Synthesis

Current state-of-the-art peptide synthesis faces significant efficiency and sustainability challenges. With demand for peptide therapeutics growing rapidly, our ability to provide these important medicines is in serious peril without a fundamental change in synthetic strategy. Inspired by nature, we developed a continuous N-C chain elongation method from N-/C- unprotected amino acids, achieving seven consecutive couplings with 96% yield per coupling. The full chain assembly is more efficient than the Fmoc protection steps required in traditional synthesis. Unlike biosynthesis, this method accepts non-canonical AAs critical for drug-like profiles. We demonstrated this platform by synthesizing decapeptide drug degarelix and a heptapeptide fragment of tirzepatide. This method reduces isolations by ~10-fold and waste generation by ~100-fold. It has the potential to transform peptide manufacturing and enable broader patient access.