Assessment of the drugability of initial malaria infection through miniaturized sporozoite assays and high-throughput screening

Marie Miglianico, Judith M. Bolscher, Martijn W. Vos, Karin J. M. Koolen, Marloes de Bruijni, Deeya S. Rajagopal, Emily Chen, Michael Kiczun, David Gray, Brice Campo, Robert W. Sauerwein, Koen J. Dechering (Lead / Corresponding author)

Research output: Contribution to journalArticlepeer-review

3 Citations (Scopus)
48 Downloads (Pure)

Abstract

The sporozoite stages of malaria parasites are the primary cause of infection of the vertebrate host and are targeted by (experimental) vaccines. Yet, little is known about their susceptibility to chemical intervention. Phenotypic high-throughput screens have not been feasible due to a lack of in vitro systems. Here we tested 78 marketed and experimental antimalarial compounds in miniaturized assays addressing sporozoite viability, gliding motility, hepatocyte traversal, and intrahepatocytic schizogony. None potently interfered with sporozoite viability or motility but ten compounds acted at the level of schizogony with IC50s < 100 nM. To identify compounds directly targeting sporozoites, we screened 81,000 compounds from the Global Health Diversity and reFRAME libraries in a sporozoite viability assay using a parasite expressing a luciferase reporter driven by the circumsporozoite promoter. The ionophore gramicidin emerged as the single hit from this screening campaign. Its effect on sporozoite viability translated into reduced gliding motility and an inability of sporozoites to invade human primary hepatocytes and develop into hepatic schizonts. While providing proof of concept for a small molecule sporontocidal mode of action, our combined data indicate that liver schizogony is more accessible to chemical intervention by (candidate) antimalarials.

Original languageEnglish
Article number216
Number of pages10
JournalCommunications Biology
Volume6
DOIs
Publication statusPublished - 23 Feb 2023

Keywords

  • Animals
  • Humans
  • Sporozoites
  • High-Throughput Screening Assays
  • Malaria/drug therapy
  • Antimalarials/pharmacology
  • Liver

ASJC Scopus subject areas

  • General Agricultural and Biological Sciences
  • General Biochemistry,Genetics and Molecular Biology
  • Medicine (miscellaneous)

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