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Chemical tools are transforming our understanding of biomolecules and living systems. Included in this group are bioorthogonal reagents-functional groups that are inert to most biological species, but can be selectively ligated with complementary probes, even in live cells and whole organisms. Applications of these tools have revealed fundamental new insights into biomolecule structure and function-information often beyond the reach of genetic approaches. In many cases, the knowledge gained from bioorthogonal probes has enabled new questions to be asked and innovative research to be pursued. Thus, the continued development and application of these tools promises to both refine our view of biological systems and facilitate new discoveries. Despite decades of achievements in bioorthogonal chemistry, limitations remain. Several reagents are too large or insufficiently stable for use in cellular environments. Many bioorthogonal groups also cross-react with one another, restricting them to singular tasks. In this Account, we describe our work to address some of the voids in the bioorthogonal toolbox. Our efforts to date have focused on small reagents with a high degree of tunability: cyclopropenes, triazines, and cyclopropenones. These motifs react selectively with complementary reagents, and their unique features are enabling new pursuits in biology. The Account is organized by common themes that emerged in our development of novel bioorthogonal reagents and reactions. First, natural product structures can serve as valuable starting points for probe design. Cyclopropene, triazine, and cyclopropenone motifs are all found in natural products, suggesting that they would be metabolically stable and compatible with a variety of living systems. Second, fine-tuning bioorthogonal reagents is essential for their successful translation to biological systems. Different applications demand different types of probes; thus, generating a collection of tools that span a continuum of reactivities and stabilities remains an important goal. We have used both computational analyses and mechanistic studies to guide the optimization of various cyclopropene and triazine probes. Along the way, we identified reagents that are chemoselective but best suited for in vitro work. Others are selective and robust enough for use in living organisms. The last section of this Account highlights the need for the continued pursuit of new reagents and reactions. Challenges exist when bioorthogonal chemistries must be used in concert, given that many exploit similar mechanisms and cannot be used simultaneously. Such limitations have precluded certain multicomponent labeling studies and other biological applications. We have relied on mechanistic and computational insights to identify mutually orthogonal sets of reactions, in addition to exploring unique genres of reactivity. The continued development of mechanistically distinct, biocompatible reactions will further diversify the bioorthogonal reaction portfolio for examining biomolecules.

Constructing New Bioorthogonal Reagents and Reactions