Nature-inspired continuous N-C chain elongation enables sustainable peptide synthesis

Abstract: Peptide synthesis is facing major global challenges in efficiency and sustainability as demand for peptide therapeutics rapidly increases. To address this, we developed a nature-inspired continuous N-to-C chain elongation platform that assembles peptides directly from unprotected amino acids, delivering high yield couplings. This new platform also features portability, scalability, and no specialized equipment required. Solid phase peptide synthesis (SPPS) has been the gold standard due to its high coupling efficiency and its ability to rapidly assemble long chains, but its C–N elongation strategy requires Fmoc-protected amino acids, which involves multiple nonproductive steps to achieve, leading to high reagent/solvent use (high PMI). An N–C elongation strategy using unprotected amino acids offers much improved atom and step economy by forming amide bonds directly. However, challenges such as epimerization, over addition, and remaining starting materials have limited its application. Here, we report a chemical N–C continuous elongation strategy using free 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 properties. Demonstrated on marketed peptide drugs, this approach 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 offer a greener and more sustainable peptide manufacturing platform and ultimately enable broader patient access.