A Click Chemistry-Based Proteomic Approach Reveals that 1,2,4-Trioxolane and Artemisinin Antimalarials Share a Common Protein Alkylation Profile

Ismail, Hanafy ORCID: https://orcid.org/0000-0002-9953-9588, Barton, Victoria E., Panchana, Matthew, Charoensutthivarakul, Sitthivut, Biagini, Giancarlo ORCID: https://orcid.org/0000-0001-6356-6595, Ward, Steve ORCID: https://orcid.org/0000-0003-2331-3192 and O'Neill, Paul M. (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, Vol 128, Issue 22, pp. 6401-6405.

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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
Subjects:	QU Biochemistry > Proteins. Amino Acids. Peptides > QU 55 Proteins QV Pharmacology > Anti-Inflammatory Agents. Anti-Infective Agents. Antineoplastic Agents > QV 256 Antimalarials QX Parasitology > Protozoa > QX 135 Plasmodia
Faculty: Department:	Biological Sciences > Department of Tropical Disease Biology Biological Sciences > Vector Biology Department
Digital Object Identifer (DOI):	https://doi.org/10.1002/anie.201512062
Depositing User:	Jessica Jones
Date Deposited:	21 Apr 2016 11:01
Last Modified:	06 Feb 2018 13:12
URI:	https://archive.lstmed.ac.uk/id/eprint/5852

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