Flexible 3D cell-based platforms for the discovery and profiling of novel drugs targeting Plasmodium hepatic infection.

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ID: 34663
2019
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Abstract
The restricted pipeline of drugs targeting the liver stage of Plasmodium infection reflects the scarcity of cell models that mimic the human hepatic phenotype and drug metabolism, as well as Plasmodium hepatic infection. Using stirred-tank culture systems, spheroids of human hepatic cell lines were generated, sustaining a stable hepatic phenotype over four weeks of culture. Spheroids were employed in the establishment of 3D Plasmodium infection platforms that relied on static or dynamic culture conditions. Plasmodium invasion and development were recapitulated in the hepatic spheroids, yielding blood-infective merozoites. The translational potential of the 3D platforms was demonstrated by comparing the in vitro minimum inhibitory concentration of M5717, a compound under clinical development, with in vivo plasma concentrations that clear liver stage P. berghei in mice. Our results show that the 3D platforms are flexible, scalable and can predict the efficacy of anti-plasmodial therapies, constituting a powerful tool for integration in drug discovery programs.
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arez2019flexibleacs Use this key to autocite in the manuscript while using SciMatic Manuscript Manager or Thesis Manager
Authors Arez, Francisca;Rebelo, Sofia;Fontinha, Diana;Simão, Daniel;Martins, Tatiana R;Machado, Marta;Fischli, Christoph;Oeuvray, Claude;Badolo, Lassina;Carrondo, Manuel J T;Rottmann, Matthias;Spangenberg, Thomas;Brito, Catarina;Greco, Beatrice;Prudêncio, Miguel;Alves, Paula M;
Journal ACS infectious diseases
Year 2019
DOI
10.1021/acsinfecdis.9b00144
URL
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