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.
Highlights
IntroductionThe last decade has witnessed unprecedented progress in reducing the incidence of Plasmodium falciparum malaria, especially in Africa where the burden of disease is greatest
The last decade has witnessed unprecedented progress in reducing the incidence of Plasmodium falciparum malaria, especially in Africa where the burden of disease is greatest.PLOS ONE | DOI:10.1371/journal.pone.0135139 August 28, 2015New Antimalarial Transmission-Blocking Molecules have the following competing interests: all authors are employed by GlaxoSmithKline
An interference assay, using a panel of 167 compounds tested at 50 μM, showed no significant inhibition confirming that the assay had identified compounds with activity against mature gametocytes, rather than the BacTiter-Glo reaction itself (S3 Table)
Summary
The last decade has witnessed unprecedented progress in reducing the incidence of Plasmodium falciparum malaria, especially in Africa where the burden of disease is greatest. New Antimalarial Transmission-Blocking Molecules have the following competing interests: all authors are employed by GlaxoSmithKline. This does not alter the authors’ adherence to PLOS ONE policies on sharing data and materials. In order to achieve the ultimate goal of eradicating malaria, more effective tools will be required. These include efficacious vaccines and innovative antimalarial drugs with novel mechanisms of action displaying efficacy against resistant parasites and transmission blocking potential
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