Simple Protein Modification Using Zwitterionic Polymer to Mitigate the Bioactivity Loss of Conjugated Insulin

Polymer–protein conjugation has been extensively explored toward a better protein drug with improved pharmacokinetics. However, a major problem with polymer–protein conjugation is that the polymers drastically reduce the bioactivity of the modified protein. There is no perfect solution to prevent the bioactivity loss, no matter the polymer is conjugated in a non‐site specific way, or a more complex site‐specific procedure. Here the authors report for the first time that when zwitterionic carboxybetaine polymer (PCB) is conjugated to insulin through simple conventional coupling chemistry. The resulting PCB–insulin does not show a significant reduction of in vitro bioactivity. The obtained PCB–insulin shows two significant advantages as a novel pharmaceutical agent. First, its therapeutic performance is remarkable. For PCB–insulin, there is a 24% increase of in vivo pharmacological activity of lowering blood glucose compared with native insulin. Such uncommonly seen increase has rarely been reported and is expected to be due to both the improved pharmacokinetics and retained bioactivity of PCB–insulin. Second, the production is simple from manufacturing standpoints. Conjugation procedure involves only one‐step coupling reaction without complex site‐specific linkage technique. The synthesized PCB–insulin conjugates do not require chromatographic separation to purify and obtain particular isoforms.