Dual Plasmepsin-Targeting Antimalarial Agents Disrupt Multiple Stages of the Malaria Parasite Life Cycle

Artemisin combination therapy (ACT) is the main treatment option for malaria, which is caused by the intracellular parasite Plasmodium. However, increased resistance to ACT highlights the importance of finding new drugs. Recently, the aspartic proteases Plasmepsin IX and X (PMIX and PMX) were identified as promising drug targets. In this study, we describe dual inhibitors of PMIX and PMX, including WM382, that block multiple stages of the Plasmodium life cycle. We demonstrate that PMX is a master modulator of merozoite invasion and direct maturation of proteins required for invasion, parasite development, and egress. Oral administration of WM382 cured mice of P. berghei and prevented blood infection from the liver. In addition, WM382 was efficacious against P. falciparum asexual infection in humanized mice and prevented transmission to mosquitoes. Selection of resistant P. falciparum in vitro was not achievable. Together, these show that dual PMIX and PMX inhibitors are promising candidates for malaria treatment and prevention. [Display omitted] •Specific compounds against P. falciparum Plasmepsin IX and X were identified•PMIX and PMX are modulators of parasite proteins for egress, invasion, and development•Anti-PMIX and anti-PMX compounds inhibit liver, blood, and mosquito stages of Plasmodium•One compound, WM382, can clear mouse models of P. berghei and P. falciparum parasites We describe inhibitors of essential aspartic proteases from malaria parasites that block multiple life cycle stages. PMIX and PMX are master modulators processing proteins required for invasion, development, and egress. Administration of WM382 cured mice of malaria infection, showing that these inhibitors are promising candidates for malaria treatment and prevention.