anisomycin and Malaria

Recent reports of increased tolerance to artemisinin derivatives--the most recently adopted class of antimalarials--have prompted a need for new treatments. The spirotetrahydro-beta-carbolines, or spiroindolones, are potent drugs that kill the blood stages of Plasmodium falciparum and Plasmodium vivax clinical isolates at low nanomolar concentration. Spiroindolones rapidly inhibit protein synthesis in P. falciparum, an effect that is ablated in parasites bearing nonsynonymous mutations in the gene encoding the P-type cation-transporter ATPase4 (PfATP4). The optimized spiroindolone NITD609 shows pharmacokinetic properties compatible with once-daily oral dosing and has single-dose efficacy in a rodent malaria model.

Topics: Adenosine Triphosphatases; Animals; Antimalarials; Cell Line; Drug Discovery; Drug Resistance; Erythrocytes; Female; Genes, Protozoan; Humans; Indoles; Malaria; Male; Mice; Models, Molecular; Mutant Proteins; Mutation; Parasitic Sensitivity Tests; Plasmodium berghei; Plasmodium falciparum; Plasmodium vivax; Protein Synthesis Inhibitors; Protozoan Proteins; Rats; Rats, Wistar; Spiro Compounds

The growing resistance to current first-line antimalarial drugs represents a major health challenge. To facilitate the discovery of new antimalarials, we have implemented an efficient and robust high-throughput cell-based screen (1,536-well format) based on proliferation of Plasmodium falciparum (Pf) in erythrocytes. From a screen of approximately 1.7 million compounds, we identified a diverse collection of approximately 6,000 small molecules comprised of >530 distinct scaffolds, all of which show potent antimalarial activity (<1.25 microM). Most known antimalarials were identified in this screen, thus validating our approach. In addition, we identified many novel chemical scaffolds, which likely act through both known and novel pathways. We further show that in some cases the mechanism of action of these antimalarials can be determined by in silico compound activity profiling. This method uses large datasets from unrelated cellular and biochemical screens and the guilt-by-association principle to predict which cellular pathway and/or protein target is being inhibited by select compounds. In addition, the screening method has the potential to provide the malaria community with many new starting points for the development of biological probes and drugs with novel antiparasitic activities.

Topics: Animals; Antimalarials; Cluster Analysis; Computational Biology; Drug Evaluation, Preclinical; Drug Resistance; Folic Acid Antagonists; Malaria; Models, Molecular; Parasites; Plasmodium falciparum; Reproducibility of Results; Structure-Activity Relationship; Tetrahydrofolate Dehydrogenase