Ismail, HM, Barton, VE, Panchana, M, Charoensutthivarakul, S, Biagini, GA, Ward, SA and O'Neill, PM 
ORCID: 0000-0003-4338-0317
(2016)
A Click Chemistry-Based Proteomic Approach Reveals that 1,2,4-Trioxolane and Artemisinin Antimalarials Share a Common Protein Alkylation Profile.
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION, 55 (22).
pp. 6401-6405.
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A Click Chemistry-Based Proteomic Approach Reveals that 1,2,4-Trioxolane and Artemisinin Antimalarials Share a Common Protein Alkylation Profile.pdf - Published version Download (1MB) |
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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.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | antimalarial, artemisinin, chemical biology, probes |
| Depositing User: | Symplectic Admin |
| Date Deposited: | 25 Nov 2016 14:37 |
| Last Modified: | 19 Jan 2023 07:25 |
| DOI: | 10.1002/anie.201512062 |
| Related URLs: | |
| URI: | https://livrepository.liverpool.ac.uk/id/eprint/3004667 |
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