Precision Conjugation: An Emerging Tool for Generating Protein–Polymer Conjugates

Abstract

Protein–polymer conjugates are increasingly being applied in biomedicine because of the unique combination of the biological activity of the proteins and the multifunctionality and flexibility of the polymers. However, traditional protein–polymer conjugation techniques suffer from some unavoidable drawbacks, including nonspecificity and low efficiency. In this Minireview, we discuss a new approach based on “precision conjugation” for the construction of the next‐generation protein–polymer conjugates in a more controlled, more efficient, and tailorable fashion for a broad range of advanced applications. In illustrating the concept, we highlight two general methods: site‐specific in situ growth and intrinsically disordered polypeptide fusion, with a focus on the in situ, efficient, and controllable formation of protein–polymer conjugates. At the end, the challenges associated with this emerging concept are further discussed.

Protein-, (Poly)peptide-, and Amino Acid-Based Nanostructures Prepared via Polymerization-Induced Self-Assembly

“…Some native proteins display undesirable properties, such as reduced stability under non-physiological conditions and enhanced susceptibility to enzymatic degradation, thus giving rise to issues such as unfavorable immunogenic reactions [ 50 ]. Protein–polymer conjugates address these issues by providing improved properties; both components render beneficial characteristics to the resulting conjugate (i.e., proteins offer good bio-functionality, whereas polymers provide increased solubility and stability, as well as improved circulation half-life and biodistribution) [ 51 ]. Hydrophilic proteins, such as bovine serum albumin (BSA) and human serum albumin (HSA), have been typically selected as the corona-forming component for preparation of amphiphilic protein–polymer conjugates due to being abundantly present in living organisms and easy to isolate and modify [ 13 , 52 , 53 ].…”

Pyridine-2,6-dicarboxaldehyde-Enabled N-Terminal In Situ Growth of Polymer–Interferon α Conjugates with Significantly Improved Pharmacokinetics and In Vivo Bioactivity

“…13,34 Although the former four methods are highly valuable, they necessitate protein engineering, which can affect protein structures and functions as well as reduce the level of protein expression. 25,26 As a complement to these methods, the N-terminal modification method is unique but versatile, as protein Ntermini are accessible on a number of natural proteins and most recombinant proteins. However, it is limited to specific amino acids at the N-terminus and to elevated reaction temperatures (typically 37 °C).…”