Design, synthesis and modelling of photoreactive chemical probes for investigating target engagement of plasmepsin IX and X in <i>Plasmodium falciparum</i>.

Lisauskaitė, Monika ORCID: 0009-0000-1364-5439, Nixon, Gemma L ORCID: 0000-0002-9730-0960, Woodley, Christopher M ORCID: 0000-0003-1311-4288, Berry, Neil G ORCID: 0000-0003-1928-0738, Coninckx, Andy ORCID: 0000-0001-9821-2746, Qie, L Charlie ORCID: 0009-0002-6325-7447, Leung, Suet C, Taramelli, Donatella ORCID: 0000-0001-5108-4492, Basilico, Nicoletta ORCID: 0000-0001-9030-1066, Parapini, Silvia ORCID: 0000-0003-2079-8892
et al (show 5 more authors) (2024) Design, synthesis and modelling of photoreactive chemical probes for investigating target engagement of plasmepsin IX and X in <i>Plasmodium falciparum</i>. RSC chemical biology, 5 (1). pp. 19-29.

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The emergence of <i>Plasmodium</i> 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 <i>Plasmodium</i> 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 <i>Plasmodium</i> 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 (IC<sub>50</sub> = 15 nM <i>versus</i> D10 <i>P. falciparum</i>) and its inhibitory effect against <i>Pf</i>PMX 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 <i>Plasmodium</i>. We expect our findings to act as a tool for future investigations on PMIX/PMX inhibition in antimalarial drug discovery.

Item Type: Article
Uncontrolled Keywords: 3404 Medicinal and Biomolecular Chemistry, 34 Chemical Sciences, Infectious Diseases, Biotechnology, Rare Diseases, Antimicrobial Resistance, Vector-Borne Diseases, Orphan Drug, Malaria, 5.1 Pharmaceuticals, 2.2 Factors relating to the physical environment, 2 Aetiology, 5 Development of treatments and therapeutic interventions, Infection, 3 Good Health and Well Being
Divisions: Faculty of Science and Engineering > School of Physical Sciences
Depositing User: Symplectic Admin
Date Deposited: 12 Jan 2024 16:51
Last Modified: 20 Jun 2024 16:32
DOI: 10.1039/d3cb00109a
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