title: Discovery of Dual-Stage Malaria Inhibitors with New Targets.
abstract: Malaria remains a major global health problem, with more than half of the world population at risk of contracting the disease and nearly a million deaths each year. Here, we report the discovery of inhibitors that target multiple stages of malaria parasite growth. To identify these inhibitors, we took advantage of the Tres Cantos Antimalarial Compound Set (TCAMS) small-molecule library, which is comprised of diverse and potent chemical scaffolds with activities against the blood stage of the malaria parasite, and investigated their effects against the elusive liver stage of the malaria parasite using a forward chemical screen. From a screen of nearly 14,000 compounds, we identified and confirmed 103 compounds as dual-stage malaria inhibitors. Interestingly, these compounds show preferential inhibition of parasite growth in liver- versus blood-stage malaria parasite assays, highlighting the drug susceptibility of this parasite form. Mode-of-action studies were completed using genetically modified and drug-resistant Plasmodium parasite strains. While we identified some compound targets as classical antimalarial pathways, such as the mitochondrial electron transport chain through cytochrome bc1 complex inhibition or the folate biosynthesis pathway, most compounds induced parasite death through as yet unknown mechanisms of action. Importantly, the identification of new chemotypes with different modes of action in killing Plasmodium parasites represents a promising opportunity for probing essential and novel molecular processes that remain to be discovered. The chemical scaffolds identified with activity against drug-resistant Plasmodium parasites represent starting points for dual-stage antimalarial development to surmount the threat of malaria parasite drug resistance.
authors.affiliation: Department of Chemistry, Duke University, Durham, North Carolina, USA.
authors.forename: Rene
authors.initials: R
authors.lastname: Raphemot
authors.affiliation: GlaxoSmithKline, Tres Cantos Medicines Development Campus, Severo Ochoa, Madrid, Spain.
authors.forename: Maria J
authors.initials: MJ
authors.lastname: Lafuente-Monasterio
authors.affiliation: GlaxoSmithKline, Tres Cantos Medicines Development Campus, Severo Ochoa, Madrid, Spain.
authors.forename: Francisco Javier
authors.initials: FJ
authors.lastname: Gamo-Benito
authors.affiliation: Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Jon
authors.initials: J
authors.lastname: Clardy
authors.affiliation: Department of Chemistry, Duke University, Durham, North Carolina, USA Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, North Carolina, USA emily.derbyshire@duke.edu.
authors.forename: Emily R
authors.initials: ER
authors.lastname: Derbyshire
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D000852:Anopheles / Q000469:parasitology; D000962:Antimalarials / Q000494:pharmacology*; D000090722:Dihydroorotate Dehydrogenase; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D056945:Hep G2 Cells / Q000187:drug effects / Q000469:parasitology; D006801:Humans; D058990:Molecular Targeted Therapy / Q000379:methods; D044925:Oxidoreductases Acting on CH-CH Group Donors / Q000235:genetics / Q000378:metabolism; D010962:Plasmodium berghei / Q000187:drug effects*; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D054852:Small Molecule Libraries / Q000494:pharmacology*
chemical_list: D000962:Antimalarials; D000090722:Dihydroorotate Dehydrogenase; D054852:Small Molecule Libraries; D044925:Oxidoreductases Acting on CH-CH Group Donors