Naude, MariskaVan Heerden, AshleighReader, JanetteVan der Watt, Mariette ElizabethNiemand, JandeliJoubert, DoreSiciliano, GiuliaAlano, PietroNjoroge, MathewChibale, KellyHerreros, EsperanzaLeroy, DidierBirkholtz, Lyn-Marie2025-02-262025-02-262024-11-15Naude, M., Van Heerden, A., Reader, J. et al. 2024, 'Eliminating malaria transmission requires targeting immature and mature gametocytes through lipoidal uptake of antimalarials', Nature Communications, vol. 15, art. 9896, pp. 1-15. https://DOI.org/10.1038/s41467-024-54144-x.2041-1723 (online)10.1038/s41467-024-54144-xhttp://hdl.handle.net/2263/101214DATA AVAILABILITY : All data generated or analyzed during this study are included in this published article (and its supplementary information files). Source data are provided with this paper.CODE AVAILABILITY : All computer codes used to analyze the data are available on GitHub (https://github.com/M2PL/Stage-specific-models-for-Pf) and Ersilia (https://github.com/ersilia-os/eos80ch; identifier eos80ch).Novel antimalarial compounds targeting both the pathogenic and transmissible stages of the human malaria parasite, Plasmodium falciparum, would greatly benefit malaria elimination strategies. However, most compounds affecting asexual blood stage parasites show severely reduced activity against gametocytes. The impact of this activity loss on a compound’s transmission-blocking activity is unclear. Here, we report the systematic evaluation of the activity loss against gametocytes and investigate the confounding factors contributing to this. A threshold for acceptable activity loss between asexual blood stage parasites and gametocytes was defined, with near-equipotent compounds required to prevent continued gametocyte maturation and onward transmission. Target abundance is not predictive of gametocytocidal activity, but instead, lipoidal uptake is the main barrier of dual activity and is influenced by distinct physicochemical properties. This study provides guidelines for the required profiles of potential dual-active antimalarial agents and facilitates the development of effective transmission-blocking compounds.en© The Author(s) 2024. This article is licensed under a Creative Commons Attribution 4.0 International License.Plasmodium falciparumMalariaElimination strategiesParasitesSDG-03: Good health and well-beingArticle