Synthesis of Polypeptides with High-Fidelity Terminal Functionalities under NCA Monomer-Starved Conditions
Lei Li,
Jie Cen,
Wenhao Pan,
Yuben Zhang,
Xuanxi Leng,
Zhengqi Tan,
Hao Yin,
Shiyong Liu
Affiliations
Lei Li
Hefei National Laboratory for Physical Sciences at the Microscale, Department of Polymer Science and Engineering, School of Chemistry and Materials Science, University of Science and Technology of China, Hefei, Anhui 230026, China
Jie Cen
Hefei National Laboratory for Physical Sciences at the Microscale, Department of Polymer Science and Engineering, School of Chemistry and Materials Science, University of Science and Technology of China, Hefei, Anhui 230026, China
Wenhao Pan
Hefei National Laboratory for Physical Sciences at the Microscale, Department of Polymer Science and Engineering, School of Chemistry and Materials Science, University of Science and Technology of China, Hefei, Anhui 230026, China
Yuben Zhang
Hefei National Laboratory for Physical Sciences at the Microscale, Department of Polymer Science and Engineering, School of Chemistry and Materials Science, University of Science and Technology of China, Hefei, Anhui 230026, China
Xuanxi Leng
Hefei National Laboratory for Physical Sciences at the Microscale, Department of Polymer Science and Engineering, School of Chemistry and Materials Science, University of Science and Technology of China, Hefei, Anhui 230026, China
Zhengqi Tan
Hefei National Laboratory for Physical Sciences at the Microscale, Department of Polymer Science and Engineering, School of Chemistry and Materials Science, University of Science and Technology of China, Hefei, Anhui 230026, China
Hao Yin
Mass Spectrometry Lab, Hefei National Laboratory for Physical Sciences at the Microscale, University of Science and Technology of China, Hefei, Anhui 230026, China
Shiyong Liu
Hefei National Laboratory for Physical Sciences at the Microscale, Department of Polymer Science and Engineering, School of Chemistry and Materials Science, University of Science and Technology of China, Hefei, Anhui 230026, China
Controlled polypeptide synthesis via α-amino acid N-carboxylic anhydride (NCA) polymerization using conventional primary amine initiators encounters two major obstacles: (i) normal amine mechanism (NAM) and activated monomer mechanism (AMM) coexist due to amine basicity and nucleophilicity and (ii) NCA is notoriously sensitive towards moisture and heat and unstable upon storage. We serendipitously discover that N-phenoxycarbonyl-functionalized α-amino acid (NPCA), a latent NCA precursor, could be polymerized solely based on NAM with high initiating efficiency by using primary amine hydrochloride as an initiator. The polymerization affords well-defined polypeptides with narrow polydispersity and high-fidelity terminal functionalities, as revealed by the clean set of MALDI-TOF MS patterns. We further demonstrate successful syntheses of random and block copolypeptides, even under open-vessel conditions. Overall, the integration of moisture-insensitive and air-tolerant NPCA precursors with stable primary amine hydrochloride initiators represents a general strategy for controlled synthesis of high-fidelity polypeptides with sophisticated functions.
