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Enhancing specificity of drug target identification with
click chemistry-based probes and quantitative proteomics
Qingsong Lin, Jigang Wang
Department of Biological Sciences, National University of Singapore,
National University of Singapore, Singapore 117543
Identification of drug targets is a crucial step towards the understanding of
the mechanism of action of the drug. It might also lead to discovery of the
potentially unrevealed actions of the drug and thus refine its future clinical
applications. We use click chemistry-based probes combined with iTRAQTM
(isobaric tags for relative and absolute quantitation) quantitative proteomics
approach to specifically identify drug targets in live cells. We have identified
the protein targets of andrographolide, a natural product with known antiinflammation and anti-cancer effects, in live cancer cells. The identified
target list not only confirmed the anti-inflammatory and anti-cancer
properties of the drug, but also revealed its potential novel application as a
tumor metastasis inhibitor. Using this strategy, combining with a cleavable
probe, we have also identified the protein targets of aspirin and its binding
sites, revealing its roles in inhibition of protein synthesis and induction of
autophagy. We have also developed a clickable probe of artemisinin and
identified over 100 covalent binding targets in malaria parasite. Our results
revealed artemisinin’s promiscuous targeting mechanism of action, as well
as its heme-dependent drug activation mechanism.