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

Current state-of-the-art peptide synthesis faces a significant global challenge in efficiency and sustainability. 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 that typically relies on C to N chain elongation and protecting groups. Inspired by nature, we developed a continuous N to C chain elongation method from N-/C- unprotected amino acids, achieving seven consecutive couplings with 96% yield per coupling without intermediate isolations. The full chain assembly is more efficient than the Fmoc protection steps required in traditional synthesis. Unlike biosynthesis, this method accepts non-canonical AAs that are 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. Longer peptides can be readily assembled with continuous fragment couplings. The platform has the potential to transform peptide manufacturing and enable broader patient access.