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


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.

SUBMITTER: Reader J 

PROVIDER: S-EPMC7801607 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature

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

Reader Janette J   van der Watt Mariëtte E ME   Taylor Dale D   Le Manach Claire C   Mittal Nimisha N   Ottilie Sabine S   Theron Anjo A   Moyo Phanankosi P   Erlank Erica E   Nardini Luisa L   Venter Nelius N   Lauterbach Sonja S   Bezuidenhout Belinda B   Horatscheck Andre A   van Heerden Ashleigh A   Spillman Natalie J NJ   Cowell Anne N AN   Connacher Jessica J   Opperman Daniel D   Orchard Lindsey M LM   Llinás Manuel M   Istvan Eva S ES   Goldberg Daniel E DE   Boyle Grant A GA   Calvo David D   Mancama Dalu D   Coetzer Theresa L TL   Winzeler Elizabeth A EA   Duffy James J   Koekemoer Lizette L LL   Basarab Gregory G   Chibale Kelly K   Birkholtz Lyn-Marié LM  

Nature communications 20210111 1


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 compound  ...[more]

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