Towards next-generation treatment options to combat Plasmodium falciparum malaria

Abstract

Malaria, which is caused by infection of red blood cells with Plasmodium parasites, can be fatal in non-immune individuals if left untreated. The recent approval of the pre-erythrocytic vaccines RTS, S/AS01 and R21/Matrix-M has ushered in hope of substantial reductions in mortality rates, especially when combined with other existing interventions. However, the efficacy of these vaccines is partial, and chemotherapy remains central to malaria treatment and control. For many antimalarial drugs, clinical efficacy has been compromised by the emergence of drug-resistant Plasmodium falciparum strains. Therefore, there is an urgent need for new antimalarial medicines to complement the existing first-line artemisinin-based combination therapies. In this Review, we discuss various opportunities to expand the present malaria treatment space, appraise the current antimalarial drug development pipeline and highlight examples of promising targets. We also discuss other approaches to circumvent antimalarial resistance and how potency against drug-resistant parasites could be retained.

Fig. 1 |. Lifecycle of Plasmodium parasites and target candidate profiles (TCP) of antimalarial drugs.

Human infection begins with the injection of fewer than 100 sporozoites into the bloodstream by a female Anopheles mosquito during a blood meal. These sporozoites migrate to the liver where they invade hepatocytes and replicate, which for Plasmodium falciparum lasts one week and results in ~10,000–30,000 merozoites per infected hepatocyte. With Plasmodium vivax, sporozoites can also form a population of dormant hypnozoites that persist in the liver for weeks to months after the primary infection, with reactivation producing subsequent waves of malaria relapse. TCP-3 and TCP-4 refer to chemoprotection, which can be achieved by targeting the motile sporozoites, their hepatic schizont forms or merozoites as they emerge into the bloodstream from the liver. Released merozoites then invade mature red blood cells (RBCs) and for P. falciparum initiate ~48-h cycles of asexual blood stage (ABS) growth, egress and reinvasion. ABS parasites, typically infecting 10⁸–10¹² RBCs, are responsible for disease manifestations; thus TCP-1 applies to antimalarials that can eliminate ABS parasites. By contrast, P. vivax preferentially invades (nucleated) reticulocytes that constitute only ~1–2% of circulating RBCs, restricting this species from attaining as high levels of parasite burden as P. falciparum. TCP-5 agents act on sexual stages that are transmitted to Anopheles mosquitoes, whereas TCP-6 agents are co-administered with an antimalarial and act against the Anopheles vector to reduce their longevity and their ability to transmit Plasmodium parasites.

Fig. 2 |. Candidate antimalarial drugs mediate their effects by disrupting processes or metabolic pathways in different subcellular organelles.

Plasmepsins IX and X are resident in the parasite rhoptry and micronemes, respectively, and are reportedly inhibited by WM4, WM382 and UCB7362. These compounds act by inhibiting the processing of plasmepsins IX and X substrates involved in egress and invasion. As the parasite matures in the erythrocyte, the parasite vacuolar and plasma membranes invaginate to form cytostomes that carry host haemoglobin into the parasite digestive vacuole. Haemoglobin-filled vesicles also perform this function. Inside the digestive vacuole, haemoglobin is digested by resident proteases to release peptides that are further processed by aminopeptidases to release smaller peptides that are shuttled out into the cytosol as a source of amino acids. Inhibitors of haemoglobin proteolysis target plasmepsins, falcipains, falcilysins and aminopeptidases. Haemoglobin degradation also liberates toxic haem that the parasite converts to inert crystalline haemozoin. Inhibitors of haem detoxification are thought to produce toxic ‘free’ haem or drug–haem complexes. The parasite plasma membrane harbours a Niemann–Pick type C-1 related protein and a P-type cation pump. Inhibitors of these transporters disrupt lipid transport and sodium ion homeostasis across this membrane. Compounds that show activity against mitochondrial processes interfere with components of the electron transport chain and/or pyrimidine biosynthesis while within the nucleus, new molecules that disrupt histone acetylation through inhibition of acetyl-CoA synthetase have been reported. In the Golgi complex, phosphatidylinositol 4-kinase (PI4K) converts phosphatidylinositol to phosphatidylinositol 4-phosphate (PI4P), which regulates effector protein recruitment and lipid-sorting events. Inhibitors of PI4K interact with its ATP-binding pocket leading to changes in PI4P pools.