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Visualizing biologically active small molecules in cells using click chemistry


Natural products and synthetic small molecules can be used to perturb, dissect and manipulate biological processes, thereby providing the basis for drug development. Over the past decades, the evolution of molecular biology protocols and microscopy techniques has made it possible to visually detect proteins in living systems with valuable spatiotemporal resolution, in which dynamic topological information has proved to be insightful. By contrast, although small molecules have become essential for biological studies, general methods to track them in cells remain underexplored. In this Review, we discuss how bioorthogonal chemistry, and click chemistry in particular, can be exploited to label and visualize almost any biologically active small molecule in cells and tissues. We review recent developments, highlighting cases in which visualizing small molecules has provided crucial mechanistic insights. This methodology is facile to implement, is versatile and is illuminating.

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The authors apologize to all those whose work could not be cited owing to space limitations. The authors thank M. Dawson, S. Britton, D. Larrieu, K. Miller, E. Zacharioudakis, A. Hienzsch and T. Mai for their contribution to the primary research described in this article. The authors thank their colleagues who developed bioorthogonal chemistry, as well as those who solidly established the use of small molecules in cell biology studies. R.R. thanks S. Balasubramanian for insightful discussions and support. R.R. is supported by the European Research Council (grant number 647973).

Reviewer information

Nature Reviews Chemistry thanks A. Huczyński and the other anonymous reviewer(s) for their contribution to the peer review of this work.

Author information

T.C., S.M. and R.R. researched data for the article, made substantial contributions to discussions of the content, wrote the article and reviewed and/or edited the manuscript before submission.

Competing interests

The authors declare no competing interests.

Correspondence to Raphaël Rodriguez.

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