Eliminating malaria transmission requires targeting immature and mature gametocytes through lipoidal uptake of antimalarials

作者：Mariska Naude, Ashleigh van Heerden, Janette Reader, Mariëtte van der Watt, Jandeli Niemand, Dorè Joubert, Giulia Siciliano, Pietro Alano, Mathew Njoroge, Kelly Chibale, Esperanza Herreros, Didier Leroy, Lyn‐Marié Birkholtz · 发表于：Nature Communications · 年份：2024 · DOI：10.1038/s41467-024-54144-x · 被引用次数：11 · 研究领域：Malaria Research and Control、Mosquito-borne diseases and control、HIV Research and Treatment

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. Most compounds active against asexual blood stage malaria parasites show reduced activity against gametocytes. Here the authors directly compare asexual and gametocytocidal activity of 80 compounds and identify physicochemical properties that influence dual activity.