A Click Chemistry‐Based Proteomic Approach Reveals that 1, 2, 4‐Trioxolane and Artemisinin Antimalarials Share a Common Protein Alkylation Profile. Issue 22 (18th April 2016)

• Record Type: Journal Article
• Authors: Ismail, Hanafy M.; Barton, Victoria E.; Panchana, Matthew; Charoensutthivarakul, Sitthivut; Biagini, Giancarlo A.; Ward, Stephen A.; O'Neill, Paul M.
• Is Part Of: Angewandte Chemie international edition. Volume 55:Issue 22(2016)
• Page Start: 6401
• Page End: 6405
• Publication Date: 2016-04-18
• Subjects: antimalarial -- artemisinin -- chemical biology -- probes; Chemistry -- Periodicals; 540
• DOI: 10.1002/anie.201512062
• Languages: English
• ISSNs: 1433-7851

Abstract

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. Abstract : Clickable 1, 2, 4‐trioxolane activity‐based protein‐profiling probes (ABPPs) were designed to retain antimalarial activity and alkylate the molecular targets of the blood stage of Plasmodium falciparum in situ. Comparison of the 1, 2, 4‐trioxolane protein alkylation signature with the corresponding artemisinin ABPPs indicates that both drug classes target key proteins in the glycolytic, hemoglobin degradation, antioxidant defence and protein synthesis pathways.