Nature-Inspired Continuous N-C Chain Elongation Enables Sustainable Peptide Synthesis
Year: 2026
Type: preprint
Abstract: 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.
Source: ChemRxiv
Authors: Jingjun Yin, Ji Qi, Zhiyan Song, Jin Zhang, Enkai Wang, Yang Cao, Xiao Wang, Fangzhou Xie, Baoqiang Wan, Qixue Yuan, Liwen Xu, Chunrui Sun, Hongming Li, Kai-Jiong Xiao, Shishi Lin, Gao Shang, Lu Wang, Jing Xu, Jiwen Jiang, Xiupeng Duan, Donghong Li, Mengli Zhang, Haijiang Nan, Fang Wang, Minyi Feng, Guiquan Liu, Louis-Charles Campeau
Language: English
Subfield: Organic Chemistry
Field: Chemistry
Domain: Physical Sciences
Open Access status: green
OpenAlex ID: W7126069274