Openvessle and Superfast NCA Polymerization to Synthesize Polypeptides

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Polypeptides can be prepared via ring-opening polymerization of α-amino acid N-carboxyanhydrides (NCAs). Conventional initiators, such as primary amines, give slow NCA polymerization, which requires multiple days to reach completion and can result in substantial side reactions, especially for very reactive NCAs. Moreover, current NCA polymerizations are very sensitive to moisture and must typically be conducted in a glove box. We have discovered that lithium bis(trimethylsilyl)amide (LiHMDS) initiate an extremely rapid NCA polymerization process that is completed within minutes or hours and can be conducted in an open vessel. 

Polypeptides have broad applications such as tissue engineering, drug delivery and antimicrobials. Preparing polypeptides via polymerization on amino acid N-carboxyanhydrides (NCAs) has been the most efficient synthetic strategy. However, NCA polymerization is notoriously sensitive to moisture. In addition, the most widely used initiator primary amine only initiate slow polymerization and provide polypeptides in short to moderate chain length. It is a long lasting desire to develop new NCA polymerization chemistry that is not sensitive to moisture, fast and ability to prepare polypeptides in long chain. 

We developed the LiHMDS-initiated open vessel NCA polymerization that addressed all above challenges. Firstly, LiHMDS can initiate NCA polymerization outside of the glovebox in open vessels on benchtop without any protection. The simple operation facilitates large scale synthesis and parallel synthesis of polypeptide libraries. Secondly, LiHMDS-initiated NCA polymerization can complete within mins to hours in sharp contrast to days when using a common primary amine as the initiator. The superfast polymerization is suitable to prepare long chain polypeptides. up to 1294-mer for poly-BLG (Mn=283400 g/mol). Thirdly, LiHMDS is a stable and commercially available initiator that is easy accessible for any lab. LiHMDS from different vendors, different lots and different synthetic methods all perform almost identical in NCA polymerization. Fourthly, both N- and C-terminal groups can be tuned easily using this NCA polymerization to obtain modifications and conjugations on polypeptides. Last but not the least, LiHMDS-initiated NCA polymerization provided polypeptides with defined secondary structures that are important for many biological activities and functions. 

NCA polymerization and resulting polypeptides have attracted more and more attentions and interests from researchers who may have background in biology, materials, drug delivery, and tissue engineering rather than organic chemistry. Therefore, we contribute the LiHMDS-initiated NCA polymerization to the scientific community to help researchers prepare polypeptides easily, without relying on glovebox and synthetic skills, and explore functions and applications of polypeptides conveniently.

Runhui Liu

Professor, East China University of Science and Technology