Reader, JanetteVan der Watt, Mariette ElizabethTaylor, DaleLe Manach, ClaireMittal, NimishaOttilie, SabineTheron, AnjoMoyo, PhanankosiErlank, EricaNardini, LuisaVenter, NeliusLauterbach, SonjaBezuidenhout, BelindaHoratscheck, AndreVan Heerden, AshleighSpillman, Natalie J.Cowell, Anne N.Connacher, Jessica I.Opperman, DanielOrchard, Lindsey M.Llinas, ManuelIstvan, Eva S.Goldberg, Daniel E.Boyle, Grant A.Calvo, DavidMancama, DaluCoetzer, Theresa L.Winzeler, Elizabeth A.Duffy, JamesKoekemoer, Lizette L.Basarab, GregoryChibale, KellyBirkholtz, Lyn-Marie2021-07-142021-07-142021-01Reader, J., van der Watt, M.E., Taylor, D. et al. Multistage and transmission-blocking targeted antimalarials discovered from the open-source MMV Pandemic Response Box. Nat Commun 12, 269 (2021). https://doi.org/10.1038/s41467-020-20629-8.2041-1723 (online)10.1038/s41467-020-20629-8http://hdl.handle.net/2263/80833Supplementary Data 1: Data of the supra-hexagonal plot in Figure 2ASupplementary Data 2: Complete dataset of all MMV PRB compounds’ activity on Plasmodium life cycle stagesSupplementary Data 3: Full SMFA dataset to support Figure 5CSupplementary Data 4: Transcriptome analysis of MMV1580488 (ML324) treated parasites to support Figure 6C.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.en© 2020 [Author et al] This is an open-access article distributed under the terms of the Creative Commons Attribution License 4.0.Antiparasitic agentsDrug discoveryParasitologyPlasmodiumMedicines for malaria venture (MMV)Life cycle stagesArticle