Unleashing the Power of Bond Cleavage Chemistry in Living Systems.

Jie Wang,Peng R Chen,Xin Wang,Xinyuan Fan

doi:10.1021/acscentsci.1c00124

Jie Wang, Peng R Chen + Show 2 more

Open Access

https://doi.org/10.1021/acscentsci.1c00124

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Abstract

Bioorthogonal cleavage chemistry has been rapidly emerging as a powerful tool for manipulation and gain-of-function studies of biomolecules in living systems. While the initial bond formation-centered bioorthogonal reactions have been widely adopted for labeling, tracing, and capturing biomolecules, the newly developed bond cleavage-enabled bioorthogonal reactions have opened new possibilities for rescuing small molecules as well as biomacromolecules in living systems, allowing multidimensional controls over biological processes in vitro and in vivo. In this Outlook, we first summarized the development and applications of bioorthogonal cleavage reactions (BCRs) that restore the functions of chemical structures as well as more complex networks, including the liberation of prodrugs, release of bioconjugates, and in situ reactivation of intracellular proteins. As we embarked on this fruitful progress, we outlined the unmet scientific needs and future directions along this exciting avenue. We believe that the potential of BCRs will be further unleashed when combined with other frontier technologies, such as genetic code expansion and proximity-enabled chemical labeling.

Highlights

Chemical reactions that are orthogonal to endogenous molecules and reactions would provide a powerful tool to dissect and manipulate biological processes within sophisticated living systems
Since the concept of bioorthogonal reactions was proposed almost two decades ago,[1] we have witnessed an explosion of interest in developing and optimizing bioorthogonal reactions such as Staudinger ligation,[2,3] Cu-catalyzed azide−alkyne cycloaddition (CuAAC),[4] strain-promoted azide−alkyne cycloaddition (SPAAC), and inverse-electron-demand Diels−Alder (IDA) cycloaddition.[5]
In 2008, the SPAAC reaction was applied to label cell surface glycans in a time-lapse manner to visualize the dynamic change in zebrafish embryos during their development, which demonstrated the high bioorthogonality of this exogenous chemical reaction to monitor delicate biological processes.[14]

Summary

■ INTRODUCTION

Chemical reactions that are orthogonal to endogenous molecules and reactions would provide a powerful tool to dissect and manipulate biological processes within sophisticated living systems. Oneto et al designed a Tz-modified hydrogel that can be implanted into tumor loci in mice enabling local activation of the TCO-caged prodrug inside the tumor.[32,119] In 2016, our group reported for the first time the IDA-based BCR for protein activation in mice, which offered a facial tool for timeresolved protein study and protein-based prodrug development in animals.[33] By using the circulatory system, small-molecule triggers can be injected into the caudal vein and activate a POI in target cells or tissues, enabling on-demand and remotecontrolled activation.

■ ACKNOWLEDGMENTS

Findings

■ REFERENCES