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

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.

SUBMITTER: Miglianico M

PROVIDER: S-EPMC9950425 | biostudies-literature | 2023 Feb

REPOSITORIES: biostudies-literature

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

Miglianico Marie M Bolscher Judith M JM Vos Martijn W MW Koolen Karin J M KJM de Bruijni Marloes M Rajagopal Deeya S DS Chen Emily E Kiczun Michael M Gray David D Campo Brice B Sauerwein Robert W RW Dechering Koen J KJ

Communications biology 20230223 1

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 sch ...[more]

PMID: 36823266

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Project description:Genotoxicity is a critical component of a comprehensive toxicological profile. The Tox21 Program used five quantitative high-throughput screening (qHTS) assays measuring some aspect of DNA damage/repair to provide information on the genotoxic potential of over 10 000 compounds. Included were assays detecting activation of p53, increases in the DNA repair protein ATAD5, phosphorylation of H2AX, and enhanced cytotoxicity in DT40 cells deficient in DNA-repair proteins REV3 or KU70/RAD54. Each assay measures a distinct component of the DNA damage response signaling network; >70% of active compounds were detected in only one of the five assays. When qHTS results were compared with results from three standard genotoxicity assays (bacterial mutation, in vitro chromosomal aberration, and in vivo micronucleus), a maximum of 40% of known, direct-acting genotoxicants were active in one or more of the qHTS genotoxicity assays, indicating low sensitivity. This suggests that these qHTS assays cannot in their current form be used to replace traditional genotoxicity assays. However, despite the low sensitivity, ranking chemicals by potency of response in the qHTS assays revealed an enrichment for genotoxicants up to 12-fold compared with random selection, when allowing a 1% false positive rate. This finding indicates these qHTS assays can be used to prioritize chemicals for further investigation, allowing resources to focus on compounds most likely to induce genotoxic effects. To refine this prioritization process, models for predicting the genotoxicity potential of chemicals that were active in Tox21 genotoxicity assays were constructed using all Tox21 assay data, yielding a prediction accuracy up to 0.83. Data from qHTS assays related to stress-response pathway signaling (including genotoxicity) were the most informative for model construction. By using the results from qHTS genotoxicity assays, predictions from models based on qHTS data, and predictions from commercial bacterial mutagenicity QSAR models, we prioritized Tox21 chemicals for genotoxicity characterization.

Dataset Information

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

Publications

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

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