The production of polypeptides via the ring-opening polymerization(ROP)of N-carboxyanhydride(NCA)is usually conducted under stringent anhydrous conditions.The ROP of proline NCA(ProNCA)for the synthesis of poly-L-proline(PLP)is particularly challenging due to the premature product precipitation as polyproline type Ⅰ helices,leading to slow reactions for up to one week,poor control of the molar mass and laborious workup.Here,we report the unexpected water-assisted controlled ROP of ProNCA,which affords well-defined PLP as polyproline Ⅱ helices in 2-5 minutes and almost-quantitative yields.Experimental and theoretical studies together suggest the as-yet-unreported role of water in facilitating proton shift,which significantly lowers the energy barrier of the chain propagation.The scope of initiators can be expanded from hydrophobic amines to encompass hydrophilic amines and thiol-bearing nucleophiles,including complex biomacromolecules such as proteins.Protein-mediated ROP of ProNCA conveniently affords various protein-PLP conjugates via a grafting-from approach.PLP modification not only preserves the biological activities of the native proteins,but also enhances their resistance to extreme conditions.Moreover,PLP modification extends the elimination half-life of asparaginase(ASNase)18-fold and mitigates the immunogenicity of wt ASNase＞250-fold(ASNase is a first-line anticancer drug for lymphoma treatment).This work provides a simple solution to a long-standing problem in PLP synthesis,and offers valuable guidance for the development of water-resistant ROP of other proline-like NCAs.The facile access to PLP can greatly boost the application potential of PLP-based functional materials for engineering industry enzymes and therapeutic proteins.

Yali Hu;Zi-You Tian;Wei Xiong;Dedao Wang;Ruichi Zhao;Yan Xie;Yu-Qin Song;Jun Zhu;Hua Lu

Beijing National Laboratory for Molecular Sciences,Center for Soft Matter Science and Engineering,Key Laboratory of Polymer Chemistry and Physics of the Ministry of Education,College of Chemistry and Molecular Engineering,Peking University,Beijing 100871,China;Peking-Tsinghua Center for Life Sciences,Academy for Advanced Interdisciplinary Studies,Peking University,Beijing 100871,China;Key Laboratory of Carcinogenesis and Translational Research(Ministry of Education),Department of Lymphoma,Peking University Cancer Hospital and Institute,Beijing 100142,China

国家科学评论（英文版）

[1]Yali Hu;Zi-You Tian;Wei Xiong;Dedao Wang;Ruichi Zhao;Yan Xie;Yu-Qin Song;Jun Zhu;Hua Lu-.Water-assisted and protein-initiated fast and controlled ring-opening polymerization of proline N-carboxyanhydride)[J].国家科学评论（英文版）,2022(08):80-90

carboxyanhydride,ProNCA,polyproline,initiators,ASNase,NCAs

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