A highly efficient and specific “grafting to” route for stable protein-polymer conjugates based on Spy chemistry

The coupling of protein and polymer utilizing grafting to method has always suffered from poor efficiency and specificity. In this work, we developed a highly efficient and specific approach for the grafting to synthesis of stable protein-polymer conjugates based on Spy chemistry. The conjugation of Spytag-terminated polymers (∼24 kDa) and genetically engineered model protein SpyCatcher-sf GFP (∼40 kDa) was completed with a slight excess of polymers (1.5 eq.) in aqueous solution within 30 min at room temperature. Furthermore, the conjugation reaction was independent of interferents and the covalent binding was shown to be resistant to boiling and remained intact for at least 3 months at 4 °C, exhibiting favorable specificity and stability. Specifically, oxidative tolerance of protein (A1AT) was highly enhanced after conjugation with Se containing polymers. This novel protein-polymer conjugation strategy is expected to develop abundant hybrid platforms for fields like diseases treatment, and provides a new view for the exploration of conjugation methods. [Display omitted] •Well-defined polymers are successful fabricated via ATRP using polypeptide Spytag as initiator.•The conjugation between protein and polymers can complete efficiently and exhibit favorable independence of interferents.•The forming covalent linkage displays favorable thermal and storage stability.•Therapeutical protein A1AT is conjugated with Se-containing polymers, which displays enhanced antioxidant activity.