Plasmodium falciparumprotein Pfs16 is a target for transmission-blocking antimalarial drug development

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Abstract

Phenotypic cell-based screens are critical to the discovery of new antimalarial lead compounds. However, identification and validation of cellular targets of lead compounds is required following discovery in a phenotypic screen. We recently discovered aPlasmodiumtransmission-blocking N-((4-hydroxychroman-4-yl)methyl)-sulfonamide (N-4HCS) compound,DDD01035881, in a phenotypic screen.DDD01035881and its potent derivatives have been shown to blockPlasmodiummale gamete formation (microgametogenesis) with nanomolar activity. Here, we synthesised a photoactivatable N-4HCS derivative, probe2, to identify the N-4HCS cellular target. Using probe2in photo-affinity labelling coupled with mass spectrometry, we identified the 16 kDaPlasmodium falciparumparasitophorous vacuole membrane protein Pfs16 as the likely cellular target of the N-4HCS series. Further validating Pfs16 as the cellular target of the N-4HCS series, the Cellular Thermal Shift Assay (CETSA) confirmed DDD01035881 stabilised Pfs16 in lysate from activated mature gametocytes. Additionally, photo-affinity labelling combined with in-gel fluorescence and immunoblot analysis confirmed the N-4HCS series interacted with Pfs16. High-resolution, widefield fluorescence and electron microscopy of N-4HCS-inhibited parasites was found to result in a cell morphology entirely consistent with targeted gene disruption ofPfs16. Taken together, these data strongly implicate Pfs16 as the target ofDDD01035881and establish the N-4HCS scaffold family as a powerful starting point from which future transmission-blocking antimalarials can be developed.

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