Site-Specific Conjugation of Polymers to Proteins

Conjugation of polymer to protein has been widely employed in therapeutics, medicine, biotechnology, and enzymatic catalysis. The synergistic effect benefits both counterparts and potentially overcomes their inherent limitations. This article reviews the strategies for the site specific synthesis of well-defined protein-polymer conjugates, aiming to provide a toolbox for the community. First, it is essential to set a definite reactive site on the protein because the position of the reaction site can directly influence the reaction activity and the bioactivity of the protein after modification. The origins of the specific functional groups on protein include the utilization of the unique natural amino acid, mutagenesis to introduce a sole reactive amino acid, chemical modification, noncanonical amino acid incorporation, and enzyme-mediated introduction of functional groups. Second, the main conjugation methods, i.e., grafting to and grafting from methods, are summarized and compared with each other. In the grafting to method, a comprehensive investigation on the reactions used to attach an end functional polymer chain to a protein is conducted according to the position of the target site and its nature. In the grafting from method, a comparison between the commonly used controlled polymerization, i.e., atom transfer radical polymerization (ATRP) and reversible addition fragmentation transfer (RAFT), is surveyed. Further, a special case where a noncovalent bond is adopted to link the protein and polymer together is investigated due to its high specificity and reversibility, typically biotin-(strept)avidin-based interactions and metal-mediated conjugation. Finally, applications of protein polymer conjugates in drug delivery, biomedicine, biosensor, and the disease-related protein self-assembly are illustrated. This precise review on the conjugation of polymer chain to protein to form well-defined protein polymer conjugates summarizes the representative strategies and may provide useful cues in the areas of biotechnology, therapeutic drugs, and biomedicine.