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

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 and Lyn-Marié Birkholtz ()
Additional contact information
Mariska Naude: Hatfield
Ashleigh van Heerden: Hatfield
Janette Reader: Hatfield
Mariëtte van der Watt: Hatfield
Jandeli Niemand: Hatfield
Dorè Joubert: Hatfield
Giulia Siciliano: viale Regina Elena 299
Pietro Alano: viale Regina Elena 299
Mathew Njoroge: Rondebosch
Kelly Chibale: Rondebosch
Esperanza Herreros: Medicines for Malaria Venture
Didier Leroy: Medicines for Malaria Venture
Lyn-Marié Birkholtz: Hatfield

Nature Communications, 2024, vol. 15, issue 1, 1-15

Abstract: Abstract 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.

Date: 2024
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DOI: 10.1038/s41467-024-54144-x

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