Antimalarial Drug Candidate: Spiroindolones were discovered as promising antimalarial drug candidates through a high-throughput screening approach that should be applicable to a range of neglected infectious diseases. Rottmann et al. (p. 1175 ; see the Perspective by Wells ) present the preclinical profile for an optimized spiroindolone drug candidate, NITD609. They obtained evidence for a decrease in drug sensitivity in strains of the malaria parasite Plasmodium falciparum bearing amino acid mutations in the P-type ATPase, indicating possible mechanisms of action and/or resistance.

Achieving the goal of malaria elimination will depend on targeting Plasmodium pathways essential across all life stages. Here we identify a lipid kinase, phosphatidylinositol-4-OH kinase (PI(4)K), as the target of imidazopyrazines, a new antimalarial compound class that inhibits the intracellular development of multiple Plasmodium species at each stage of infection in the vertebrate host. Imidazopyrazines demonstrate potent preventive, therapeutic, and transmission-blocking activity in rodent malaria models, are active against blood-stage field isolates of the major human pathogens P. falciparum and P. vivax, and inhibit liver-stage hypnozoites in the simian parasite P. cynomolgi. We show that imidazopyrazines exert their effect through inhibitory interaction with the ATP-binding pocket of PI(4)K, altering the intracellular distribution of phosphatidylinositol-4-phosphate. Collectively, our data define PI(4)K as a key Plasmodium vulnerability, opening up new avenues of target-based discovery to identify drugs with an ideal activity profile for the prevention, treatment and elimination of malaria.

The antiplasmodial activity of a series of spirotetrahydro β-carbolines is described. Racemic spiroazepineindole (1) was identified from a phenotypic screen on wild type Plasmodium falciparum with an in vitro IC₅₀ of 90 nM. Structure−activity relationships for the optimization of 1 to compound 20a (IC₅₀ = 0.2 nM) including the identification of the active 1R,3S enantiomer and elimination of metabolic liabilities is presented. Improvement of the pharmacokinetic profile of the series translated to exceptional oral efficacy in the P. berghei infected malaria mouse model where full cure was achieved in four of five mice with three daily doses of 30 mg/kg.

Most malaria drug development focuses on parasite stages detected in red blood cells, even though, to achieve eradication, next-generation drugs active against both erythrocytic and exo-erythrocytic forms would be preferable. We applied a multifactorial approach to a set of >4000 commercially available compounds with previously demonstrated blood-stage activity (median inhibitory concentration < 1 micromolar) and identified chemical scaffolds with potent activity against both forms. From this screen, we identified an imidazolopiperazine scaffold series that was highly enriched among compounds active against Plasmodium liver stages. The orally bioavailable lead imidazolopiperazine confers complete causal prophylactic protection (15 milligrams/kilogram) in rodent models of malaria and shows potent in vivo blood-stage therapeutic activity. The open-source chemical tools resulting from our effort provide starting points for future drug discovery programs, as well as opportunities for researchers to investigate the biology of exo-erythrocytic forms.

The var gene family of Plasmodium falciparum encodes the variant surface antigen Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1). PfEMP1 is considered an important pathogenicity factor in P. falciparum infection because it mediates cytoadherence to host cell endothelial receptors. var genes can be grouped into three major groups, A, B, and C, and the conserved var genes, var1-4 , according to sequence similarities in coding and noncoding upstream regions. Using real-time quantitative PCR in a study conducted in Tanzania, the var transcript abundances of the different var gene groups were compared among patients with severe, uncomplicated, and asymptomatic malaria. Transcripts of var group A and B genes were more abundant in patients with severe malaria than in patients with uncomplicated malaria. In general, the transcript abundances of var group A and B genes were higher for children with clinical malaria than for children with asymptomatic infections. The var group C and var1 -like transcript abundances were similar between the three sample groups. A transcript abundance pattern similar to that for var group A was observed for var2csa and var3 -like genes. These results suggest that substantial and systematic differences in var gene expression exist between different clinical presentations.