Chemoselective Reagents for the Traceless Bioreversible Modification of Native Proteins

Nature utilizes bioreversible post-translational modifications (PTMs) to spatiotemporally diversify protein function. Mimicking Nature's approach, chemists have developed a variety of chemoselective regents for traceless, bioreversible modification of native proteins. These strategies have found utility in the development of reversible covalent inhibitors and degraders as well as the synthesis of functional protein conjugates for delivery into cells. This Viewpoint provides a snapshot of such tools, which currently cover Cys, Ser, Thr, Lys, Asp, and Glu residues and the N terminus. Additionally, we explore how bioreversible reagents, originally developed by research communities with differing objectives, can be utilized synergistically. Looking forward, we discuss the need for developing bioreversible reagents for labeling His, Tyr, Arg, Trp, Asn, Gln, and Met residues and the C-terminus as well as the installation of dynamic PTMs. Finally, to broaden the applicability of these tools, we point out the importance of developing modular release scaffolds with tunable release times and responsiveness to multiple endogenous triggers. We anticipate that this Viewpoint will catalyze further research and technological breakthroughs in this rapidly evolving field.