Issue 5, 2016

Chemical proteomics approaches for identifying the cellular targets of natural products

Abstract

Covering: 2010 up to 2016

Deconvoluting the mode of action of natural products and drugs remains one of the biggest challenges in chemistry and biology today. Chemical proteomics is a growing area of chemical biology that seeks to design small molecule probes to understand protein function. In the context of natural products, chemical proteomics can be used to identify the protein binding partners or targets of small molecules in live cells. Here, we highlight recent examples of chemical probes based on natural products and their application for target identification. The review focuses on probes that can be covalently linked to their target proteins (either via intrinsic chemical reactivity or via the introduction of photocrosslinkers), and can be applied “in situ” – in living systems rather than cell lysates. We also focus here on strategies that employ a click reaction, the copper-catalysed azide–alkyne cycloaddition reaction (CuAAC), to allow minimal functionalisation of natural product scaffolds with an alkyne or azide tag. We also discuss ‘competitive mode’ approaches that screen for natural products that compete with a well-characterised chemical probe for binding to a particular set of protein targets. Fuelled by advances in mass spectrometry instrumentation and bioinformatics, many modern strategies are now embracing quantitative proteomics to help define the true interacting partners of probes, and we highlight the opportunities this rapidly evolving technology provides in chemical proteomics. Finally, some of the limitations and challenges of chemical proteomics approaches are discussed.

Graphical abstract: Chemical proteomics approaches for identifying the cellular targets of natural products

Associated articles

Article information

Article type
Review Article
Submitted
05 Jan 2016
First published
21 Apr 2016
This article is Open Access
Creative Commons BY license

Nat. Prod. Rep., 2016,33, 681-708

Author version available

Chemical proteomics approaches for identifying the cellular targets of natural products

M. H. Wright and S. A. Sieber, Nat. Prod. Rep., 2016, 33, 681 DOI: 10.1039/C6NP00001K

This article is licensed under a Creative Commons Attribution 3.0 Unported Licence. You can use material from this article in other publications without requesting further permissions from the RSC, provided that the correct acknowledgement is given.

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