PfATP4 inhibitors in the Medicines for Malaria Venture Malaria Box and Pathogen Box block the schizont-to-ring transition by inhibiting egress rather than invasion

Abstract

The cation efflux pump Plasmodium falciparum ATPase 4 (PfATP4) maintains Na+ homeostasis in malaria parasites and has been implicated in the mechanism of action of many structurally diverse antimalarial agents, including >7% of the antimalarial compounds in the Medicines for Malaria Venture’s ‘Malaria Box’ and ‘Pathogen Box’. Recent screens of the ‘Malaria Box’ and ‘Pathogen Box’ revealed that many PfATP4 inhibitors prevent parasites from exiting their host red blood cell (egress) or entering new host cells (invasion), suggesting that these compounds may have additional molecular targets involved in egress or invasion. Here, we demonstrate that five PfATP4 inhibitors reduce egress but not invasion. These compounds appear to inhibit egress by blocking the activation of protein kinase G, an enzyme that, once stimulated, rapidly activates parasite egress. We establish a direct link between egress and PfATP4 function by showing that the inhibition of egress is attenuated in a Na+-depleted environment and in parasites with a mutation in pfatp4. Finally, we show that PfATP4 inhibitors induce host cell lysis when administered prior to the completion of parasite replication. Since host cell lysis mimics egress but is not followed by invasion, this phenomenon likely explains why several PfATP4 inhibitors were previously classified as invasion inhibitors. Collectively, our results confirm that PfATP4-mediated Na+ efflux is critical to the regulation of parasite egress.

Aryl amino acetamides prevent the development ofPlasmodium falciparumrings via inhibition of the lipid transfer protein PfSTART1

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Amoebicidal Effect of COVID Box Molecules against Acanthamoeba: A Study of Cell Death

“…In this sense, the “Medicines for Malaria Venture” (MMV) is considered a pioneer in the drug repurposing strategy by proposing their malaria-designed box for further diseases. The organization “Medicines for Malaria Venture” (MMV) has compiled libraries of various drugs known to exhibit in vitro anti-plasmodium activity and made them available for research all over the world to test them against other pathogens [ 7 ]. Until now, four open access boxes have been launched: the Malaria Box, the Pathogen Box, the Pandemic Response Box and the COVID Box [ 8 ].…”

Bioprospection of Selected Plant Secondary Metabolites as Modulators of the Proteolytic Activity of Plasmodium falciparum Plasmepsin V

“…The life cycle of P. falciparum is comprehensive, with an asexual replication in human red blood cells (RBC), where most of the current drugs have their targets [ 12 ]. Following the invasion of RBC by merozoites, the parasite differentiates from the ring to the trophozoite and later to the schizont stage [ 13 ]. During the trophozoite stage, the parasite heavily relies on the uptake of nutrients from the host cells [ 14 ].…”