Abstract
We developed a novel series of antimalarial compounds based on a 4-cyano-3-methylisoquinoline. Our lead compound MB14 achieved modest inhibition of the growth in vitro of the human malaria parasite, Plasmodium falciparum. To identify its biological target we selected for parasites resistant to MB14. Genome sequencing revealed that all resistant parasites bore a single point S374R mutation in the sodium (Na+) efflux transporter PfATP4. There are many compounds known to inhibit PfATP4 and some are under preclinical development. MB14 was shown to inhibit Na+ dependent ATPase activity in parasite membranes, consistent with the compound targeting PfATP4 directly. PfATP4 inhibitors cause swelling and lysis of infected erythrocytes, attributed to the accumulation of Na+ inside the intracellular parasites and the resultant parasite swelling. We show here that inhibitor-induced lysis of infected erythrocytes is dependent upon the parasite protein RhopH2, a component of the new permeability pathways that are induced by the parasite in the erythrocyte membrane. These pathways mediate the influx of Na+ into the infected erythrocyte and their suppression via RhopH2 knockdown limits the accumulation of Na+ within the parasite hence protecting the infected erythrocyte from lysis. This study reveals a role for the parasite-induced new permeability pathways in the mechanism of action of PfATP4 inhibitors.
Highlights
The brief period in the malaria parasite’s life-cycle in which the merozoite-stage parasite egresses from its host erythrocyte to infect another erythrocyte presents many novel drug targets
To find the biological target of the 4-cyano-3-methylisoquinoline MB14 compound in P. falciparum we selected for genetic resistance and identified a S374R mutation in the parasite’s plasma membrane Na+ efflux pump PfATP4
On the basis of homology modelling of PfATP4, based on the known structure of the related human Ca2+ ion pump, Sarco/Endoplasmic Reticulum Ca2+-ATPase (SERCA), the resistance-conferring S374R mutation identified here is predicted to be on the end of transmembrane helix 3
Summary
The brief period in the malaria parasite’s life-cycle in which the merozoite-stage parasite egresses from its host erythrocyte to infect another erythrocyte presents many novel drug targets. Both MB14 and cipargamin induced lysis of infected erythrocytes, probably due to the osmotic swelling of the intracellular parasite as it accumulates Na+ following inhibition of PfATP429.
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