title: A Click Chemistry-Based Proteomic Approach Reveals that 1,2,4-Trioxolane and Artemisinin Antimalarials Share a Common Protein Alkylation Profile.
abstract: In spite of the recent increase in endoperoxide antimalarials under development, it remains unclear if all these chemotypes share a common mechanism of action. This is important since it will influence cross-resistance risks between the different classes. Here we investigate this proposition using novel clickable 1,2,4-trioxolane activity based protein-profiling probes (ABPPs). ABPPs with potent antimalarial activity were able to alkylate protein target(s) within the asexual erythrocytic stage of Plasmodium falciparum (3D7). Importantly, comparison of the alkylation fingerprint with that generated from an artemisinin ABPP equivalent confirms a highly conserved alkylation profile, with both endoperoxide classes targeting proteins in the glycolytic, hemoglobin degradation, antioxidant defence, protein synthesis and protein stress pathways, essential biological processes for plasmodial survival. The alkylation signatures of the two chemotypes show significant overlap (ca. 90 %) both qualitatively and semi-quantitatively, suggesting a common mechanism of action that raises concerns about potential cross-resistance liabilities.
authors.affiliation: Research Centre for Drugs and Diagnostics, Liverpool School of Tropical Medicine, Pembroke Place, Liverpool, L3 5QA, UK.
authors.forename: Hanafy M
authors.initials: HM
authors.lastname: Ismail
authors.affiliation: Department of Chemistry, University of Liverpool, Liverpool, L69 7ZD, UK.
authors.forename: Victoria E
authors.initials: VE
authors.lastname: Barton
authors.affiliation: Research Centre for Drugs and Diagnostics, Liverpool School of Tropical Medicine, Pembroke Place, Liverpool, L3 5QA, UK.
authors.forename: Matthew
authors.initials: M
authors.lastname: Panchana
authors.affiliation: Department of Chemistry, University of Liverpool, Liverpool, L69 7ZD, UK.
authors.forename: Sitthivut
authors.initials: S
authors.lastname: Charoensutthivarakul
authors.affiliation: Research Centre for Drugs and Diagnostics, Liverpool School of Tropical Medicine, Pembroke Place, Liverpool, L3 5QA, UK.
authors.forename: Giancarlo A
authors.initials: GA
authors.lastname: Biagini
authors.affiliation: Research Centre for Drugs and Diagnostics, Liverpool School of Tropical Medicine, Pembroke Place, Liverpool, L3 5QA, UK.
authors.forename: Stephen A
authors.initials: SA
authors.lastname: Ward
authors.affiliation: Department of Chemistry, University of Liverpool, Liverpool, L69 7ZD, UK. pmoneill@liv.ac.uk.
authors.forename: Paul M
authors.initials: PM
authors.lastname: O'Neill
mesh_terms: D000478:Alkylation; D000962:Antimalarials / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D037621:Artemisinins / Q000737:chemistry / Q000494:pharmacology*; D057930:Click Chemistry; D006571:Heterocyclic Compounds / Q000737:chemistry / Q000494:pharmacology*; D015394:Molecular Structure; D021261:Parasitic Sensitivity Tests; D010963:Plasmodium falciparum / Q000187:drug effects*; D011506:Proteins / Q000138:chemical synthesis* / Q000737:chemistry; D040901:Proteomics
chemical_list: C503429:1,2,4-trioxane; D000962:Antimalarials; D037621:Artemisinins; D006571:Heterocyclic Compounds; D011506:Proteins; C031327:artemisinin
keywords: antimalarial; artemisinin; chemical biology; probes