Discrete, Chiral Polymer-Insulin Conjugates.

Polymer conjugation has been widely used to improve the stability and pharmacokinetics of therapeutic biomacromolecules; however, conventional methods to generate such conjugates often use disperse and/or achiral polymers with limited functionality. The heterogeneity of such conjugates may lead to manufacturing variability, poorly controlled biological performance, and limited ability to optimize structure-property relationships. Here, using insulin as a model therapeutic polypeptide, we introduce a strategy for the synthesis of polymer-protein conjugates based on discrete, chiral polymers synthesized through iterative exponential growth (IEG). These conjugates eliminate manufacturing variables originating from polymer dispersity and poorly controlled absolute configuration. Moreover, they offer tunable molecular features, such as conformational rigidity, that can be modulated to impact protein function, enabling faster or longer-lasting blood glucose responses in diabetic mice when compared to PEGylated insulin and the commercial insulin variant Lantus. Furthermore, IEG-insulin conjugates showed no signs of decreased activity, immunogenicity, or toxicity following repeat dosing. This work represents a significant step toward the synthesis of precise synthetic polymer-biopolymer conjugates and reveals that fine tuning of synthetic polymer structure may be used to optimize such conjugates in the future.