A series of cationic polypeptide imidazolium conjugates were prepared by ring-opening polymerization (ROP) of γ-4-(3chloropropoxycarbonyl)benzyl-L -glutamic acid-based N-carboxyanhydride (CPBLG-NCA) initiated by various mono-or diamine initiators and subsequent side-chain modification with high grafting efficiency. Rapid and controlled ROP was achieved by polymerizing CPBLG-NCA in a dichloromethane/NaHCO 3 /H 2 O solvent mixture with the amine initiators. The resulting polypeptides bearing imidazolium iodide pendants showed reversible upper critical solution temperature (UCST)-type thermoresponsive properties in both ethanol and DI water while the polypeptides with tetrafluoroborate counter-anions showed a UCST in phosphate buffer saline (PBS). The cloud point temperature (T cp ) in ethanol and aqueous solutions can be tuned by both molecular weight and the end-or linkage-groups in the main chain. The cationic polypeptides showed good antibacterial activity against Staphylococcus aureus and low hemolysis. Our results provide a facile and rapid ROP strategy to develop new families of stimuli-responsive polypeptides with tunable properties as well as antibacterial polypeptides with optimized selectivity.

Antimicrobial polypeptides are promising mimics of antimicrobial peptides (AMPs) with low risks of antimicrobial resistance (AMR). Polypeptides with facile and efficient production, high antimicrobial activity, and low toxicity toward mammalian cells are highly desirable for practical applications. Herein, triblock copolypeptides with chloro groups (PPG n -PCPBLG m ) and different main-chain lengths were synthesized via an ultrafast ring-opening polymerization (ROP) using a macroinitiator, namely poly­(propylene glycol) bis­(2-aminopropyl ether), and purified or nonpurified monomer (i.e., CPBLG-NCA). PPG n -PCPBLG m with 90 amino acid residues can be readily prepared within 300 s. Imidazolium-based block copolypeptides (PPG n -PIL m ) were facilely prepared via nucleophilic substitution of PPG n -PCPBLG m with NaN3 and subsequent “click” chemistry. α-Helical PPG n -PIL m can self-assemble into nanostructured and cationic micelles which displayed highly potent antimicrobial activity and low hemolysis. The top-performing material, namely PPG34-PIL70, showed low minimum inhibitory concentration (MIC) against both Gram-positive S. aureus and Gram-negative E. coli (25 μg mL–1). It also displayed low toxicity against mouse embryonic fibroblast (NIH 3T3) and human embryonic kidney (293T) cells at 2× MIC.

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