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A high-throughput in vitro translation screen towards discovery of novel antimalarial protein translation inhibitors

Hella Baumann, Holly Matthews, Mengqiao Li, Jenny J. Hu, Keith R. Willison, Jake Baum
doi: https://doi.org/10.1101/248740
Hella Baumann
1 Department of Life Sciences, Imperial College London, London, UK.
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Holly Matthews
1 Department of Life Sciences, Imperial College London, London, UK.
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Mengqiao Li
1 Department of Life Sciences, Imperial College London, London, UK.
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Jenny J. Hu
1 Department of Life Sciences, Imperial College London, London, UK.
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Keith R. Willison
2 Department of Chemistry, Imperial College London, London, UK.
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Jake Baum
1 Department of Life Sciences, Imperial College London, London, UK.
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ABSTRACT

Drugs that target protein synthesis are well-validated for use as antimicrobials, yet specific high throughput (HTP) methods to screen for those targeting malaria are lacking. Here, we have developed a cell free in vitro translation (IVT) assay for the human malaria parasite, Plasmodium falciparum, which reconstitutes the native parasite protein translation machinery. Combining clarified IVT lysate with a click beetle luciferase reporter gene fused to untranslated regions of Pf histidine-rich proteins (hrp)-2 and 3, the HTP IVT assay accurately reports protein translation in a 384-well plate format using a standard spectrofluorometer. We validate the assay as effective in detecting compounds targeting the ribosome, ribosome co-factors (elongation factor 2) and cytosolic tRNA synthetases as well as its ability to find translation inhibitors in a blind screen using a high-density assay format amenable for high throughput. This demonstrates an ability to reconstitute the breadth of the parasite eukaryotic protein translation machinery in vitro and use it as a powerful platform for antimalarial drug discovery.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted January 16, 2018.
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A high-throughput in vitro translation screen towards discovery of novel antimalarial protein translation inhibitors
Hella Baumann, Holly Matthews, Mengqiao Li, Jenny J. Hu, Keith R. Willison, Jake Baum
bioRxiv 248740; doi: https://doi.org/10.1101/248740
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A high-throughput in vitro translation screen towards discovery of novel antimalarial protein translation inhibitors
Hella Baumann, Holly Matthews, Mengqiao Li, Jenny J. Hu, Keith R. Willison, Jake Baum
bioRxiv 248740; doi: https://doi.org/10.1101/248740

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