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

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 vi...

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Autores principales: Miglianico, Marie, Bolscher, Judith M., Vos, Martijn W., Koolen, Karin J. M., de Bruijni, Marloes, Rajagopal, Deeya S., Chen, Emily, Kiczun, Michael, Gray, David, Campo, Brice, Sauerwein, Robert W., Dechering, Koen J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9950425/
https://www.ncbi.nlm.nih.gov/pubmed/36823266
http://dx.doi.org/10.1038/s42003-023-04599-3
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author Miglianico, Marie
Bolscher, Judith M.
Vos, Martijn W.
Koolen, Karin J. M.
de Bruijni, Marloes
Rajagopal, Deeya S.
Chen, Emily
Kiczun, Michael
Gray, David
Campo, Brice
Sauerwein, Robert W.
Dechering, Koen J.
author_facet Miglianico, Marie
Bolscher, Judith M.
Vos, Martijn W.
Koolen, Karin J. M.
de Bruijni, Marloes
Rajagopal, Deeya S.
Chen, Emily
Kiczun, Michael
Gray, David
Campo, Brice
Sauerwein, Robert W.
Dechering, Koen J.
author_sort Miglianico, Marie
collection PubMed
description 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.
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spelling pubmed-99504252023-02-25 Assessment of the drugability of initial malaria infection through miniaturized sporozoite assays and high-throughput screening Miglianico, Marie Bolscher, Judith M. Vos, Martijn W. Koolen, Karin J. M. de Bruijni, Marloes Rajagopal, Deeya S. Chen, Emily Kiczun, Michael Gray, David Campo, Brice Sauerwein, Robert W. Dechering, Koen J. Commun Biol Article 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. Nature Publishing Group UK 2023-02-23 /pmc/articles/PMC9950425/ /pubmed/36823266 http://dx.doi.org/10.1038/s42003-023-04599-3 Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Miglianico, Marie
Bolscher, Judith M.
Vos, Martijn W.
Koolen, Karin J. M.
de Bruijni, Marloes
Rajagopal, Deeya S.
Chen, Emily
Kiczun, Michael
Gray, David
Campo, Brice
Sauerwein, Robert W.
Dechering, Koen J.
Assessment of the drugability of initial malaria infection through miniaturized sporozoite assays and high-throughput screening
title Assessment of the drugability of initial malaria infection through miniaturized sporozoite assays and high-throughput screening
title_full Assessment of the drugability of initial malaria infection through miniaturized sporozoite assays and high-throughput screening
title_fullStr Assessment of the drugability of initial malaria infection through miniaturized sporozoite assays and high-throughput screening
title_full_unstemmed Assessment of the drugability of initial malaria infection through miniaturized sporozoite assays and high-throughput screening
title_short Assessment of the drugability of initial malaria infection through miniaturized sporozoite assays and high-throughput screening
title_sort assessment of the drugability of initial malaria infection through miniaturized sporozoite assays and high-throughput screening
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9950425/
https://www.ncbi.nlm.nih.gov/pubmed/36823266
http://dx.doi.org/10.1038/s42003-023-04599-3
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