Exploring the mode of action of MMV1580843 against Plasmodium falciparum

Abstract

Although malaria is both preventable and curable, it is a parasitic disease with the highest fatality rate in history, causing over half a million deaths worldwide each year, with 95 % of the cases occurring in Africa. Female Anopheles mosquitoes act as vectors for the malaria parasite. Plasmodium is transmitted to a human host when a female Anopheles mosquito feeds on the individual. In turn, humans infected with the malaria parasite can transmit the parasite back to another mosquito, perpetuating the parasite’s life cycle. The presence of both insecticide and therapeutic drug resistance to current antimalarials is an ongoing threat. Therefore, it is crucial that the next generation of antimalarials include compounds with unique modes of action and exhibiting high barriers to resistance development. Blocking transmission is essential for malaria elimination, given that current drugs primarily target asexual parasites or sporozoites and liver stages. The lower number and non-replicating nature of gametocytes render the development of resistance to transmission-blocking antimalarials highly improbable. Gametocyte-specific antimalarials are presumed to target unique biological processes compared to compounds targeting asexual parasites, reflecting the fundamental difference in the biology associated with asexual proliferation and gametocyte differentiation. A key drawback of phenotypic screening of candidate antimalarials is the lack of knowledge regarding the mode of action of a compound, which is the bottleneck of drug discovery and development. While current target identification strategies predominantly focus on the asexual stages of the parasite life cycle, there is a noticeable gap in knowledge regarding the mode of action of gametocyte-specific antimalarials. MMV1580843, a unique chemotype, is a structurally diverse and potent transmission-blocking compound, showing stage-specific activity towards non-proliferative gametocytes. This TCP-5 (target candidate profile-5, transmission-blocking) selective compound, with a potential novel mode of action in Plasmodium, was investigated here. This project thus aimed to determine the mode of action of MMV1580843 against P. falciparum late-stage gametocytes through biochemical approaches. The findings presented in this study point towards the mitochondria of late-stage gametocytes being the target of MMV1580843, supported by investigations involving fluorescent indicators and cross-reactivity with antimalarials having confirmed modes of action. The results of this research exhibit a promising step forward in elucidating the mode of action of a gametocyte-specific antimalarial, providing a foundation for the development of targeted interventions to disrupt malaria transmission. By bridging the existing gap in knowledge and proposing an innovative strategy, this study contributes to the ongoing efforts in the global fight against malaria.