Science, published online 17 November 2011, doi:10.1126/science.1211936

The malaria parasites from Plasmodium species have both a liver stage (EEF or sporozoite stage) and a blood stage in human hosts. Because EEFs of certain Plasmodium strains can remain dormant for long periods and disease symptoms originate during the blood stage, therapeutics that can eliminate parasites of both stages are needed, yet most drugs target only the blood-stage parasites. To find drugs that might inhibit multiple parasite stages, Meister et al. screened a library of 5,697 compounds known to be active against P. falciparum blood stages. In a high-content imaging assay of sporozoite-infected cultured liver cells, the authors found 275 compounds that are structurally unrelated to known antimalarial scaffolds and decrease parasite size within cells after infection. They then used a hypergeometric mean function to determine which of the 2,715 independent chemical-scaffold clusters in the original library were fully represented among the hits, identifying quinazoline, pyrazolopyrimidine and imidazolopiperazine scaffold clusters as promising. A structure-activity relationship analysis of the imidazolopiperazine scaffold yielded compounds that are active against both parasite stages and have high potencies and desirable pharmacokinetic properties. By sequencing resistance mutations, the authors identified one target for three of the imidazolopiperazine compounds as an uncharacterized seven-transmembrane-domain–containing protein. As targets of other hits are also most likely distinct from known drug targets, as shown by the authors, these may represent new opportunities for eradicating malarial infections by arresting parasite development.