Abstract
Malaria remains a significant contributor to global human mortality, and roughly half the world’s population is at risk for infection with Plasmodium spp. parasites. Aggressive control measures have reduced the global prevalence of malaria significantly over the past decade. However, resistance to available antimalarials continues to spread, including resistance to the widely used artemisinin-based combination therapies. Novel antimalarial compounds and therapeutic targets are greatly needed. This review will briefly discuss several promising current antimalarial development projects, including artefenomel, ferroquine, cipargamin, SJ733, KAF156, MMV048, and tafenoquine. In addition, we describe recent large-scale genetic and resistance screens that have been instrumental in target discovery. Finally, we highlight new antimalarial targets, which include essential transporters and proteases. These emerging antimalarial compounds and therapeutic targets have the potential to overcome multi-drug resistance in ongoing efforts toward malaria elimination.
Highlights
Malaria has posed a risk to human life since the origin of our species
This multifaceted approach to the antimalarial development pipeline provides assurance that new antimalarials will contribute to broad approaches of malaria control
The current antimalarial compounds under development have great potential, malaria control efforts will benefit from continued dissection of parasite biology
Summary
Malaria has posed a risk to human life since the origin of our species. Despite this long history, it was not until 1880 that French army surgeon Charles Louis Alphonse Laveran discovered intraerythrocytic parasites in the blood of a patient with malaria[1]. A large forward genetic screen in P. falciparum parasites recently identified more than 2,680 genes that are likely essential for asexual blood-stage growth[66]. Treatment with 49c inhibits asexual, sexual, and liver-stage development, indicating that 49c or other PMIX or PMX inhibitors may have value to both treat symptomatic malaria and block transmission[71] Together, these observations provide compelling evidence that PMIX and PMX are promising targets for antimalarial development. Rab11a has very low genetic diversity when sequenced in 2,000 Plasmodium clinical isolates, and only one nonsynonymous mutation has been identified[97] These features suggest that Rab11a may represent a promising target because of both its prenylation and interactions with essential signaling pathways within the parasite. Because SUB1 and SERA6 are essential for asexual blood-stage growth and orthologues are found in other Plasmodium species[98], compounds that inhibit these proteins may be useful in treating multiple types of malarial disease
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