Chemistry for Covalent Modification of Endogenous/Native Proteins: From Test Tubes to Complex Biological Systems

Chemical modification of proteins provides powerful tools to realize a broad range of exciting biological applications, including the development of new classes of biopharmaceuticals and functional studies of individual proteins in complex biological systems. Numerous strategies for linking desired chemical probes with target proteins have been developed in the last two decades, with most exploiting genetic protein engineering and/or bio-orthogonal chemistry that utilizes unnatural amino acids incorporated into proteins. Modification of native proteins in test tubes and biological contexts by site-specific and target-selective approaches remains challenging because appropriate organic chemistry to carry out such modifications is currently limited. Nonetheless, a variety of promising strategies have appeared recently that address this grand challenge in chemical biology. These new chemistries yield native protein-based well-defined bioconjugations, specific labeling of endogenous proteins in various biological crude milieus, and the establishment of chemical proteomics as a new research area in protein science. In this Perspective, we focus on recent remarkable progress in chemistry for native protein modification. We survey chemical characteristics of the methods and describe briefly these advanced applications to address unsolved biological issues. Current limitations and future directions of this research field are also discussed.