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Multistage and transmission-blocking targeted antimalarials discovered from the open-source MMV pandemic response box

Reader, J.
van der Watt, M.
Taylor, D.
Le Manach, C.
Mittal, N.
Ottilie, S.
Theron, A.
Moyo, P.
Erlank, E.
Nardini, L.
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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.
Description
Date
2021-01-11
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Publisher
Springer Nature
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Keywords
Antimalarial , Pandemic , Open-source MMV
Citation
Reader J, van der Watt ME, Taylor D, Le Manach C, Mittal N, Ottilie S, Theron A, Moyo P, Erlank E, Nardini L, Venter N, Lauterbach S, Bezuidenhout B, Horatscheck A, van Heerden A, Spillman NJ, Cowell AN, Connacher J, Opperman D, Orchard LM, Llinás M, Istvan ES, Goldberg DE, Boyle GA, Calvo D, Mancama D, Coetzer TL, Winzeler EA, Duffy J, Koekemoer LL, Basarab G, Chibale K, Birkholtz L-M. Multistage and transmission-blocking targeted antimalarials discovered from the open-source MMV Pandemic Response Box. Nature Communications. 2021;12(1):269. doi: 10.1038/s41467-020-20629-8.
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