Design, synthesis and modelling of photoreactive chemical probes for investigating target engagement of plasmepsin IX and X in Plasmodium falciparum

Lisauskaitė, Monika, Nixon, Gemma L., Woodley, Christopher M., Berry, Neil G., Coninckx, Andy, Qie, L. Charlie, Leung, Suet C., Taramelli, Donatella, Basilico, Nicoletta, Parapini, Silvia, Ward, Steve ORCID: https://orcid.org/0000-0003-2331-3192, Vadas, Oscar, Soldati-Favre, Dominique, Hong, W. David and O'Neill, Paul M. (2023) 'Design, synthesis and modelling of photoreactive chemical probes for investigating target engagement of plasmepsin IX and X in Plasmodium falciparum'. RSC Chemical Biology, Vol 5, Issue 1, pp. 19-29.

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Abstract

The emergence of Plasmodium parasite resistance to current front-line antimalarial treatments poses a serious threat to global malaria control and highlights the necessity for the development of therapeutics with novel targets and mechanisms of action. Plasmepsins IX and X (PMIX/PMX) have been recognised as highly promising targets in Plasmodium due to their contribution to parasite's pathogenicity. Recent research has demonstrated that dual PMIX/PMX inhibition results in the impairment of multiple parasite's life cycle stages, which is an important feature in drug resistance prevention. Herein we report novel hydroxyethylamine photoaffinity labelling (PAL) probes, designed for PMIX/PMX target engagement and proteomics experiments in Plasmodium parasites. The prepared probes have both a photoreactive group (diazirine or benzophenone) for covalent attachment to target proteins, and a terminal alkyne handle allowing their use in bioorthogonal ligation. One of the synthesised benzophenone probes was shown to be highly promising as demonstrated by its outstanding antimalarial potency (IC50 = 15 nM versus D10 P. falciparum) and its inhibitory effect against PfPMX in an enzymatic assay. Molecular docking and molecular dynamics studies show that the inclusion of the benzophenone and alkyne handle does not alter the binding mode compared to the parent compound. The photoaffinity probe can be used in future chemical proteomics studies to allow hydroxyethylamine drug scaffold target identification and validation in Plasmodium. We expect our findings to act as a tool for future investigations on PMIX/PMX inhibition in antimalarial drug discovery.

Item Type:	Article
Subjects:	WC Communicable Diseases > Tropical and Parasitic Diseases > WC 695 Parasitic diseases (General) WC Communicable Diseases > Tropical and Parasitic Diseases > WC 750 Malaria
Faculty: Department:	Biological Sciences > Department of Tropical Disease Biology
Digital Object Identifer (DOI):	https://doi.org/10.1039/d3cb00109a
SWORD Depositor:	JISC Pubrouter
Depositing User:	JISC Pubrouter
Date Deposited:	13 Nov 2023 15:34
Last Modified:	16 Feb 2024 15:23
URI:	https://archive.lstmed.ac.uk/id/eprint/23461

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