Multistage and transmission-blocking targeted antimalarials discovered from the open-source MMV Pandemic Response Box

Janette Reader, Mariëtte E. van der Watt, Dale Taylor, Claire Le Manach, Nimisha Mittal, Sabine Ottilie, Anjo Theron, Phanankosi Moyo, Erica Erlank, Luisa Nardini, Nelius Venter, Sonja Lauterbach, Belinda Bezuidenhout, Andre Horatscheck, Ashleigh van Heerden, Natalie J. Spillman, Anne N. Cowell, Jessica Connacher, Daniel Opperman, Lindsey M. Orchard, Manuel Llinás, Eva S. Istvan, Daniel E. Goldberg, Grant A. Boyle, David Calvo, Dalu Mancama, Theresa L. Coetzer, Elizabeth A. Winzeler, James Duffy, Lizette L. Koekemoer, Gregory Basarab, Kelly Chibale and Lyn-Marié Birkholtz ()
Additional contact information
Janette Reader: University of Pretoria
Mariëtte E. van der Watt: University of Pretoria
Dale Taylor: University of Cape Town
Claire Le Manach: University of Cape Town
Nimisha Mittal: University of California San Diego
Sabine Ottilie: University of California San Diego
Anjo Theron: Council for Scientific and Industrial Research
Phanankosi Moyo: University of Pretoria
Erica Erlank: University of the Witwatersrand, and Centre for Emerging Zoonotic and Parasitic Diseases, National Institute for Communicable Diseases of the National Health Laboratory Service
Luisa Nardini: University of the Witwatersrand, and Centre for Emerging Zoonotic and Parasitic Diseases, National Institute for Communicable Diseases of the National Health Laboratory Service
Nelius Venter: University of the Witwatersrand, and Centre for Emerging Zoonotic and Parasitic Diseases, National Institute for Communicable Diseases of the National Health Laboratory Service
Sonja Lauterbach: University of the Witwatersrand
Belinda Bezuidenhout: University of the Witwatersrand
Andre Horatscheck: University of Cape Town
Ashleigh van Heerden: University of Pretoria
Natalie J. Spillman: Washington University
Anne N. Cowell: University of California San Diego
Jessica Connacher: University of Pretoria
Daniel Opperman: University of Pretoria
Lindsey M. Orchard: Pennsylvania State University
Manuel Llinás: Pennsylvania State University
Eva S. Istvan: Washington University
Daniel E. Goldberg: Washington University
Grant A. Boyle: University of Cape Town
David Calvo: GlaxoSmithKline (GSK)
Dalu Mancama: Council for Scientific and Industrial Research
Theresa L. Coetzer: University of the Witwatersrand
Elizabeth A. Winzeler: University of California San Diego
James Duffy: International Center Cointrin
Lizette L. Koekemoer: University of the Witwatersrand, and Centre for Emerging Zoonotic and Parasitic Diseases, National Institute for Communicable Diseases of the National Health Laboratory Service
Gregory Basarab: University of Cape Town
Kelly Chibale: University of Cape Town
Lyn-Marié Birkholtz: University of Pretoria

Nature Communications, 2021, vol. 12, issue 1, 1-15

Abstract: Abstract Chemical matter is needed to target the divergent biology associated with the different life cycle stages of Plasmodium. Here, we report the parallel de novo screening of the Medicines for Malaria Venture (MMV) Pandemic Response Box against Plasmodium asexual and liver stage parasites, stage IV/V gametocytes, gametes, oocysts and as endectocides. Unique chemotypes were identified with both multistage activity or stage-specific activity, including structurally diverse gametocyte-targeted compounds with potent transmission-blocking activity, such as the JmjC inhibitor ML324 and the antitubercular clinical candidate SQ109. Mechanistic investigations prove that ML324 prevents histone demethylation, resulting in aberrant gene expression and death in gametocytes. Moreover, the selection of parasites resistant to SQ109 implicates the druggable V-type H+-ATPase for the reduced sensitivity. Our data therefore provides an expansive dataset of compounds that could be redirected for antimalarial development and also point towards proteins that can be targeted in multiple parasite life cycle stages.

Date: 2021
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DOI: 10.1038/s41467-020-20629-8

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