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.
