Synthesis of Polypeptides with High-Fidelity Terminal Functionalities under NCA Monomer-Starved Conditions.
Synthesis of Polypeptides with High-Fidelity Terminal Functionalities under NCA Monomer-Starved Conditions.
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DOI：
10.34133/2021/9826046
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发表时间：
2021
期刊：
影响因子：
--
通讯作者：
Liu S
中科院分区：
文献类型：
--
作者：
Li L;Cen J;Pan W;Zhang Y;Leng X;Tan Z;Yin H;Liu S
利用传统伯胺引发剂通过α-氨基酸-羧酸酐（NCA）聚合合成受控多肽面临两个主要障碍：(1)由于胺的碱性和亲核性，正常胺机制（NAM）和活化单体机制（AMM）共存；(2)NCA对湿热非常敏感，储存不稳定。我们偶然发现n -苯氧羰基功能化α-氨基酸（NPCA）是一种潜在的NCA前体，可以用盐酸伯胺作为引发剂，以NAM为基础进行聚合，并具有很高的引发效率。聚合提供了定义明确的多肽，具有狭窄的多分散性和高保真的末端功能，正如MALDI-TOF MS模式所揭示的那样。我们进一步证明了即使在开放容器条件下也能成功合成随机和嵌段共肽。总之，将湿不敏感和耐空气的NPCA前体与稳定的盐酸伯胺引发剂相结合，代表了一种控制合成具有复杂功能的高保真多肽的一般策略。
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.
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