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

Sabrina Yahiya, View ORCID ProfileCharlie N. Saunders, Ursula Straschil, Oliver J. Fischer, View ORCID ProfileAinoa Rueda-Zubiaurre, View ORCID ProfileSilvia Haase, Gema Vizcay-Barrena, Sarah Jordan, Sarah Hassan, View ORCID ProfileMichael J. Delves, View ORCID ProfileEdward W. Tate, View ORCID ProfileAnna Barnard, View ORCID ProfileMatthew J. Fuchter, View ORCID ProfileJake Baum
doi: https://doi.org/10.1101/2021.06.14.448287
Sabrina Yahiya
1Department of Life Sciences, Imperial College London, Sir Alexander Fleming Building, Exhibition Road, South Kensington, London, SW7 2AZ, UK
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Charlie N. Saunders
1Department of Life Sciences, Imperial College London, Sir Alexander Fleming Building, Exhibition Road, South Kensington, London, SW7 2AZ, UK
2Department of Chemistry, Imperial College London, Molecular Sciences Research Hub, White City Campus, Wood Lane, London, W12 OBZ, UK
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Ursula Straschil
1Department of Life Sciences, Imperial College London, Sir Alexander Fleming Building, Exhibition Road, South Kensington, London, SW7 2AZ, UK
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Oliver J. Fischer
2Department of Chemistry, Imperial College London, Molecular Sciences Research Hub, White City Campus, Wood Lane, London, W12 OBZ, UK
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Ainoa Rueda-Zubiaurre
2Department of Chemistry, Imperial College London, Molecular Sciences Research Hub, White City Campus, Wood Lane, London, W12 OBZ, UK
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Silvia Haase
1Department of Life Sciences, Imperial College London, Sir Alexander Fleming Building, Exhibition Road, South Kensington, London, SW7 2AZ, UK
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Gema Vizcay-Barrena
3Centre for Ultrastructural Imaging, New Hunt’s House, Guy’s Campus, King’s College London, London, SE1 1UL, UK
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Sarah Jordan
1Department of Life Sciences, Imperial College London, Sir Alexander Fleming Building, Exhibition Road, South Kensington, London, SW7 2AZ, UK
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Sarah Hassan
2Department of Chemistry, Imperial College London, Molecular Sciences Research Hub, White City Campus, Wood Lane, London, W12 OBZ, UK
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Michael J. Delves
1Department of Life Sciences, Imperial College London, Sir Alexander Fleming Building, Exhibition Road, South Kensington, London, SW7 2AZ, UK
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Edward W. Tate
2Department of Chemistry, Imperial College London, Molecular Sciences Research Hub, White City Campus, Wood Lane, London, W12 OBZ, UK
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Anna Barnard
2Department of Chemistry, Imperial College London, Molecular Sciences Research Hub, White City Campus, Wood Lane, London, W12 OBZ, UK
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Matthew J. Fuchter
2Department of Chemistry, Imperial College London, Molecular Sciences Research Hub, White City Campus, Wood Lane, London, W12 OBZ, UK
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Jake Baum
1Department of Life Sciences, Imperial College London, Sir Alexander Fleming Building, Exhibition Road, South Kensington, London, SW7 2AZ, UK
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  • For correspondence: jake.baum@imperial.ac.uk
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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 a Plasmodium transmission-blocking N-((4-hydroxychroman-4-yl)methyl)-sulfonamide (N-4HCS) compound, DDD01035881, in a phenotypic screen. DDD01035881 and its potent derivatives have been shown to block Plasmodium male gamete formation (microgametogenesis) with nanomolar activity. Here, we synthesised a photoactivatable N-4HCS derivative, probe 2, to identify the N-4HCS cellular target. Using probe 2 in photo-affinity labelling coupled with mass spectrometry, we identified the 16 kDa Plasmodium falciparum parasitophorous 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 of Pfs16. Taken together, these data strongly implicate Pfs16 as the target of DDD01035881 and establish the N-4HCS scaffold family as a powerful starting point from which future transmission-blocking antimalarials can be developed.

Competing Interest Statement

The authors have declared no competing interest.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license.
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Posted June 14, 2021.
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Plasmodium falciparum protein Pfs16 is a target for transmission-blocking antimalarial drug development
Sabrina Yahiya, Charlie N. Saunders, Ursula Straschil, Oliver J. Fischer, Ainoa Rueda-Zubiaurre, Silvia Haase, Gema Vizcay-Barrena, Sarah Jordan, Sarah Hassan, Michael J. Delves, Edward W. Tate, Anna Barnard, Matthew J. Fuchter, Jake Baum
bioRxiv 2021.06.14.448287; doi: https://doi.org/10.1101/2021.06.14.448287
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Plasmodium falciparum protein Pfs16 is a target for transmission-blocking antimalarial drug development
Sabrina Yahiya, Charlie N. Saunders, Ursula Straschil, Oliver J. Fischer, Ainoa Rueda-Zubiaurre, Silvia Haase, Gema Vizcay-Barrena, Sarah Jordan, Sarah Hassan, Michael J. Delves, Edward W. Tate, Anna Barnard, Matthew J. Fuchter, Jake Baum
bioRxiv 2021.06.14.448287; doi: https://doi.org/10.1101/2021.06.14.448287

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