title: Luciferase-Based, High-Throughput Assay for Screening and Profiling Transmission-Blocking Compounds against Plasmodium falciparum Gametocytes.
abstract: The discovery of new antimalarial drugs able to target both the asexual and gametocyte stages ofPlasmodium falciparumis critical to the success of the malaria eradication campaign. We have developed and validated a robust, rapid, and cost-effective high-throughput reporter gene assay to identify compounds active against late-stage (stage IV and V) gametocytes. The assay, which is suitable for testing compound activity at incubation times up to 72 h, demonstrates excellent quality and reproducibility, with averageZ' values of 0.85 ± 0.01. We used the assay to screen more than 10,000 compounds from three chemically diverse libraries. The screening outcomes highlighted the opportunity to use collections of compounds with known activity against the asexual stages of the parasites as a starting point for gametocytocidal activity detection in order to maximize the chances of identifying gametocytocidal compounds. This assay extends the capabilities of our previously reported luciferase assay, which tested compounds against early-stage gametocytes, and opens possibilities to profile the activities of gametocytocidal compounds over the entire course of gametocytogenesis.
authors.affiliation: Discovery Biology, Eskitis Institute for Drug Discovery, Griffith University, Nathan, Queensland, Australia.
authors.forename: Leonardo
authors.initials: L
authors.lastname: Lucantoni
authors.affiliation: Department of Microbiology and Immunology, Columbia University College of Physicians and Surgeons, New York, New York, USA Division of Infectious Diseases, Department of Medicine, Columbia University College of Physicians and Surgeons, New York, New York, USA.
authors.forename: David A
authors.initials: DA
authors.lastname: Fidock
authors.affiliation: Discovery Biology, Eskitis Institute for Drug Discovery, Griffith University, Nathan, Queensland, Australia v.avery@griffith.edu.au.
authors.forename: Vicky M
authors.initials: VM
authors.lastname: Avery
mesh_terms: D000605:Amino Alcohols / Q000494:pharmacology; D000634:Aminoquinolines / Q000494:pharmacology; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D000962:Antimalarials / Q000494:pharmacology*; D037621:Artemisinins / Q000494:pharmacology; D055808:Drug Discovery; D004912:Erythrocytes / Q000187:drug effects / Q000469:parasitology; D005260:Female; D005493:Folic Acid Antagonists / Q000494:pharmacology; D015870:Gene Expression; D017930:Genes, Reporter; D057166:High-Throughput Screening Assays / Q000592:standards*; D006801:Humans; D020128:Inhibitory Concentration 50; D008018:Life Cycle Stages / Q000187:drug effects*; D008156:Luciferases / Q000235:genetics / Q000378:metabolism; D008163:Luminescent Measurements; D008297:Male; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000254:growth & development; D054852:Small Molecule Libraries / Q000494:pharmacology
chemical_list: D000605:Amino Alcohols; D000634:Aminoquinolines; D000900:Anti-Bacterial Agents; D000962:Antimalarials; D037621:Artemisinins; D005493:Folic Acid Antagonists; D054852:Small Molecule Libraries; D008156:Luciferases