Flexible 3d cell-based platforms for the discovery and profiling of novel drugs targeting plasmodium hepatic infection

Francisca Arez, Sofia P. Rebelo, Diana Fontinha, Daniel Simaõ, Tatiana R. Martins, Marta MacHado, Christoph Fischli, Claude Oeuvray, Lassina Badolo, Manuel J.T. Carrondo, Matthias Rottmann, Thomas Spangenberg, Catarina Brito, Beatrice Greco, Miguel Prudêncio, Paula M. Alves

Research output: Contribution to journalArticle

4 Citations (Scopus)

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 4 weeks of culture. Spheroids were employed in the establishment of 3D Plasmodium berghei infection platforms that relied on static or dynamic culture conditions. P. berghei 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 and scalable and can predict the efficacy of antiplasmodial therapies, constituting a powerful tool for integration in drug discovery programs.

Original languageEnglish
Pages (from-to)1831-1842
Number of pages12
JournalACS Infectious Diseases
Volume5
Issue number11
DOIs
Publication statusPublished - 8 Nov 2019

Keywords

  • 3D cell models
  • drug discovery
  • in vitro
  • liver stage infection
  • malaria
  • Plasmodium

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