Precision in protein chemical modification and total synthesis

Chemically engineered biomacromolecules (e.g., proteins) offer great opportunities to investigate fundamental chemical biology and develop novel therapeutics. With the increasing depth of chemical biology studies, tailored proteins with one or more site-specific modifications are in high demand for an unambiguous discovery. However, the development of such a chemoselective strategy for protein chemical modification is a great challenge due to the complexity of diverse functional groups presenting in proteins. As the top-down strategy, the developed bioconjugations applying the kinetic recognition of the desired single amino acid residue by covalent or non-covalent interactions sophisticatedly enable the site-specific modifications in endogenous proteins. As the bottom-up strategy, chemical protein synthesis through chemoselective ligations is advantageous for constructing customized proteins with multiple atomically precise modifications. In this tutorial review, the chemoselectivity barrier and solutions in the construction of tailor-made proteins by protein modification and chemical protein synthesis will be discussed.