title: A New Set of Chemical Starting Points with Plasmodium falciparum Transmission-Blocking Potential for Antimalarial Drug Discovery.
abstract: The discovery of new antimalarials with transmission blocking activity remains a key issue in efforts to control malaria and eventually eradicate the disease. Recently, high-throughput screening (HTS) assays have been successfully applied to Plasmodium falciparum asexual stages to screen millions of compounds, with the identification of thousands of new active molecules, some of which are already in clinical phases. The same approach has now been applied to identify compounds that are active against P. falciparum gametocytes, the parasite stage responsible for transmission. This study reports screening results for the Tres Cantos Antimalarial Set (TCAMS), of approximately 13,533 molecules, against P. falciparum stage V gametocytes. Secondary confirmation and cytotoxicity assays led to the identification of 98 selective molecules with dual activity against gametocytes and asexual stages. Hit compounds were chemically clustered and analyzed for appropriate physicochemical properties. The TCAMS chemical space around the prioritized hits was also studied. A selection of hit compounds was assessed ex vivo in the standard membrane feeding assay and demonstrated complete block in transmission. As a result of this effort, new chemical structures not connected to previously described antimalarials have been identified. This new set of compounds may serve as starting points for future drug discovery programs as well as tool compounds for identifying new modes of action involved in malaria transmission.
authors: GlaxoSmithKline, Tres Cantos Medicines Development Campus-Diseases of the Developing World, Severo Ochoa 2, Tres Cantos, 28760, Madrid, Spain; Universidad Nacional de Educación a Distancia (UNED), C/ Senda del Rey 11, 28040, Madrid, Spain.
authors: Maria Jesus
authors: MJ
authors: Almela
authors: GlaxoSmithKline, Tres Cantos Medicines Development Campus-Diseases of the Developing World, Severo Ochoa 2, Tres Cantos, 28760, Madrid, Spain.
authors: Sonia
authors: S
authors: Lozano
authors: GlaxoSmithKline, Tres Cantos Medicines Development Campus-Diseases of the Developing World, Severo Ochoa 2, Tres Cantos, 28760, Madrid, Spain.
authors: Joël
authors: J
authors: Lelièvre
authors: GlaxoSmithKline, Basic Research Center, Computational Chemistry Department, C/ Santiago Grisolía 4, Tres Cantos, 28760, Madrid, Spain.
authors: Gonzalo
authors: G
authors: Colmenarejo
authors: GlaxoSmithKline, Tres Cantos Medicines Development Campus-Diseases of the Developing World, Severo Ochoa 2, Tres Cantos, 28760, Madrid, Spain.
authors: José Miguel
authors: JM
authors: Coterón
authors: GlaxoSmithKline, Tres Cantos Medicines Development Campus-Diseases of the Developing World, Severo Ochoa 2, Tres Cantos, 28760, Madrid, Spain.
authors: Janneth
authors: J
authors: Rodrigues
authors: GlaxoSmithKline, Tres Cantos Medicines Development Campus-Diseases of the Developing World, Severo Ochoa 2, Tres Cantos, 28760, Madrid, Spain.
authors: Carolina
authors: C
authors: Gonzalez
authors: GlaxoSmithKline, Tres Cantos Medicines Development Campus-Diseases of the Developing World, Severo Ochoa 2, Tres Cantos, 28760, Madrid, Spain.
authors: Esperanza
authors: E
authors: Herreros
mesh_terms: D000962:Antimalarials / Q000494:pharmacology* / Q000627:therapeutic use*; D055808:Drug Discovery; D004353:Drug Evaluation, Preclinical; D057166:High-Throughput Screening Assays; D006801:Humans; D020128:Inhibitory Concentration 50; D008163:Luminescent Measurements / Q000379:methods; D016778:Malaria, Falciparum / Q000188:drug therapy* / Q000635:transmission*; D021261:Parasitic Sensitivity Tests; D010963:Plasmodium falciparum / Q000187:drug effects*; D015203:Reproducibility of Results; D054852:Small Molecule Libraries
chemical_list: D000962:Antimalarials; D054852:Small Molecule Libraries