A chemical proteomics approach for the search of pharmacological targets of the antimalarial clinical candidate albitiazolium in Plasmodium falciparum using photocrosslinking and click chemistry

PLoS One. 2014 Dec 3;9(12):e113918. doi: 10.1371/journal.pone.0113918. eCollection 2014.


Plasmodium falciparum is responsible for severe malaria which is one of the most prevalent and deadly infectious diseases in the world. The antimalarial therapeutic arsenal is hampered by the onset of resistance to all known pharmacological classes of compounds, so new drugs with novel mechanisms of action are critically needed. Albitiazolium is a clinical antimalarial candidate from a series of choline analogs designed to inhibit plasmodial phospholipid metabolism. Here we developed an original chemical proteomic approach to identify parasite proteins targeted by albitiazolium during their native interaction in living parasites. We designed a bifunctional albitiazolium-derived compound (photoactivable and clickable) to covalently crosslink drug-interacting parasite proteins in situ followed by their isolation via click chemistry reactions. Mass spectrometry analysis of drug-interacting proteins and subsequent clustering on gene ontology terms revealed parasite proteins involved in lipid metabolic activities and, interestingly, also in lipid binding, transport, and vesicular transport functions. In accordance with this, the albitiazolium-derivative was localized in the endoplasmic reticulum and trans-Golgi network of P. falciparum. Importantly, during competitive assays with albitiazolium, the binding of choline/ethanolamine phosphotransferase (the enzyme involved in the last step of phosphatidylcholine synthesis) was substantially displaced, thus confirming the efficiency of this strategy for searching albitiazolium targets.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antimalarials / chemistry
  • Antimalarials / metabolism
  • Antimalarials / pharmacology
  • Binding, Competitive
  • Click Chemistry
  • Cross-Linking Reagents / chemistry
  • Diacylglycerol Cholinephosphotransferase / metabolism
  • Endoplasmic Reticulum / metabolism
  • Humans
  • Malaria, Falciparum / metabolism
  • Malaria, Falciparum / parasitology
  • Malaria, Falciparum / prevention & control*
  • Models, Chemical
  • Molecular Structure
  • Plasmodium falciparum / drug effects*
  • Plasmodium falciparum / metabolism
  • Protein Binding
  • Proteome / chemistry
  • Proteome / metabolism*
  • Proteomics / methods*
  • Protozoan Proteins / chemistry
  • Protozoan Proteins / metabolism*
  • Thiazoles / chemistry
  • Thiazoles / metabolism
  • Thiazoles / pharmacology*
  • trans-Golgi Network / metabolism


  • 1,12-bis(4-methyl-5-(2-hydroxyethyl)thiazol-3-ium-3-yl)dodecane
  • Antimalarials
  • Cross-Linking Reagents
  • Proteome
  • Protozoan Proteins
  • Thiazoles
  • Diacylglycerol Cholinephosphotransferase

Grant support

This work was supported the European Community (FP7/EviMalar Network of Excellence No. 242095; http://www.evimalar.org/), by Sanofi (www.sanofi.fr/) and by a InnoMad grant from the Eurobiomed competitiveness cluster (Région Languedoc-Roussillon/FEDER/OSEO) (http://www.eurobiomed.org/). DMPV received funding from InnoMad (Eurobiomed) and Sanofi. AB received funding from InnoMad (Eurobiomed). HC received funding from FP7/EviMalar Network of Excellence. The funders provided support in the form of salaries for authors (DMPV and LF), but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.