Dual Self-Promoted Ring-Opening Polymerization towards Cationic Polypeptoids with Stable Helices
Kunyu Gan1, Ronald N. Zuckermann2, Ning Zhao3,4, Sunting Xuan1(宣孙婷)*, Zhengbiao Zhang1,5(张正彪)*
1State and Local Joint Engineering Laboratory for Novel Functional Polymeric Materials, Jiangsu Key Laboratory of Advanced Functional Polymer Design and Application, Suzhou Key Laboratory of Macromolecular Design and Precision Synthesis, College of Chemistry, Chemical Engineering and Materials Science, Soochow University, Suzhou 215123, China
2The Molecular Foundry, Lawrence Berkeley National Laboratory, 1Cyclotron Road, Berkeley, California 94720, USA
3College of Pharmaceutical Sciences, Soochow University, Suzhou215123, China
4Leherna Therapeutics, Suzhou 215123, China
5State Key Laboratory of Radiation Medicine and Protection, Soochow University, Suzhou 215123, China
Angew. Chem. Int. Ed. 2026, 65, e21129
Abstract: Cationic helices play crucial roles in various biological processes. While polypeptides containing lysine and guanidine side chains are among the most prevalent cationic polymers, their helical structures are often unstable due to side-chain electrostatic repulsion. Here, bulky, chiral tertiary amine side chains were incorporated into polypeptoids by controlled ring-opening polymerization, inducing achiral backbones into stable helices. Despite the highly steric side chains, the cyclic monomer underwent efficient polymerization via a dual self-promoted mechanism involving side chain-mediated proton transfer and helix-induced acceleration. Subsequent quaternization yielded structurally diverse polyproline-I-like helical cationic polypeptoids. Unlike conventional polypeptides where cationic side chains typically disrupt helicity, these cationic polypeptoids exhibited remarkably stable helices. The cationic side chains stabilize the helices by enforcing cis-amide backbone conformations through two key interactions: 1) C─H···O hydrogen bonding between side chains and backbone; 2) steric hindrance of side chains. Preliminary studies demonstrated that cationic helical polypeptoids exhibited significantly lower cytotoxicity and faster cellular uptake kinetics compared to the conventional cationic polypeptide poly(l-lysine). The dual self-promoted synthesis, coupled with cationic side chain-mediated helix stabilization, provides new insights for designing advanced functional polymers. Moreover, these cationic polypeptoids, with robust helices, low cytotoxicity and high cellular uptake, hold great promise for various biological applications.
Article information: https://doi.org/10.1002/anie.202521129