TY - JOUR
T1 - Multistage and transmission-blocking targeted antimalarials discovered from the open-source MMV Pandemic Response Box
AU - Reader, Janette
AU - van der Watt, Mariëtte E.
AU - Taylor, Dale
AU - Le Manach, Claire
AU - Mittal, Nimisha
AU - Ottilie, Sabine
AU - Theron, Anjo
AU - Moyo, Phanankosi
AU - Erlank, Erica
AU - Nardini, Luisa
AU - Venter, Nelius
AU - Lauterbach, Sonja
AU - Bezuidenhout, Belinda
AU - Horatscheck, Andre
AU - van Heerden, Ashleigh
AU - Spillman, Natalie J.
AU - Cowell, Anne N.
AU - Connacher, Jessica
AU - Opperman, Daniel
AU - Orchard, Lindsey M.
AU - Llinás, Manuel
AU - Istvan, Eva S.
AU - Goldberg, Daniel E.
AU - Boyle, Grant A.
AU - Calvo, David
AU - Mancama, Dalu
AU - Coetzer, Theresa L.
AU - Winzeler, Elizabeth A.
AU - Duffy, James
AU - Koekemoer, Lizette L.
AU - Basarab, Gregory
AU - Chibale, Kelly
AU - Birkholtz, Lyn Marié
N1 - Publisher Copyright:
© 2021, The Author(s).
PY - 2021/12/1
Y1 - 2021/12/1
N2 - 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.
AB - 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.
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U2 - 10.1038/s41467-020-20629-8
DO - 10.1038/s41467-020-20629-8
M3 - Article
C2 - 33431834
AN - SCOPUS:85099193777
SN - 2041-1723
VL - 12
JO - Nature communications
JF - Nature communications
IS - 1
M1 - 269
ER -