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Chemoprotective antimalarials identified through quantitative high-throughput screening of Plasmodium blood and liver stage parasites
The spread of Plasmodium falciparum parasites resistant to most first-line antimalarials creates an imperative to enrich the drug discovery pipeline, preferably with curative compounds that can also act prophylactically. We report a phenotypic quantitative high-throughput screen (qHTS), based on con...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7822874/ https://www.ncbi.nlm.nih.gov/pubmed/33483532 http://dx.doi.org/10.1038/s41598-021-81486-z |
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author | Dorjsuren, Dorjbal Eastman, Richard T. Wicht, Kathryn J. Jansen, Daniel Talley, Daniel C. Sigmon, Benjamin A. Zakharov, Alexey V. Roncal, Norma Girvin, Andrew T. Antonova-Koch, Yevgeniya Will, Paul M. Shah, Pranav Sun, Hongmao Klumpp-Thomas, Carleen Mok, Sachel Yeo, Tomas Meister, Stephan Marugan, Juan Jose Ross, Leila S. Xu, Xin Maloney, David J. Jadhav, Ajit Mott, Bryan T. Sciotti, Richard J. Winzeler, Elizabeth A. Waters, Norman C. Campbell, Robert F. Huang, Wenwei Simeonov, Anton Fidock, David A. |
author_facet | Dorjsuren, Dorjbal Eastman, Richard T. Wicht, Kathryn J. Jansen, Daniel Talley, Daniel C. Sigmon, Benjamin A. Zakharov, Alexey V. Roncal, Norma Girvin, Andrew T. Antonova-Koch, Yevgeniya Will, Paul M. Shah, Pranav Sun, Hongmao Klumpp-Thomas, Carleen Mok, Sachel Yeo, Tomas Meister, Stephan Marugan, Juan Jose Ross, Leila S. Xu, Xin Maloney, David J. Jadhav, Ajit Mott, Bryan T. Sciotti, Richard J. Winzeler, Elizabeth A. Waters, Norman C. Campbell, Robert F. Huang, Wenwei Simeonov, Anton Fidock, David A. |
author_sort | Dorjsuren, Dorjbal |
collection | PubMed |
description | The spread of Plasmodium falciparum parasites resistant to most first-line antimalarials creates an imperative to enrich the drug discovery pipeline, preferably with curative compounds that can also act prophylactically. We report a phenotypic quantitative high-throughput screen (qHTS), based on concentration–response curves, which was designed to identify compounds active against Plasmodium liver and asexual blood stage parasites. Our qHTS screened over 450,000 compounds, tested across a range of 5 to 11 concentrations, for activity against Plasmodium falciparum asexual blood stages. Active compounds were then filtered for unique structures and drug-like properties and subsequently screened in a P. berghei liver stage assay to identify novel dual-active antiplasmodial chemotypes. Hits from thiadiazine and pyrimidine azepine chemotypes were subsequently prioritized for resistance selection studies, yielding distinct mutations in P. falciparum cytochrome b, a validated antimalarial drug target. The thiadiazine chemotype was subjected to an initial medicinal chemistry campaign, yielding a metabolically stable analog with sub-micromolar potency. Our qHTS methodology and resulting dataset provides a large-scale resource to investigate Plasmodium liver and asexual blood stage parasite biology and inform further research to develop novel chemotypes as causal prophylactic antimalarials. |
format | Online Article Text |
id | pubmed-7822874 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-78228742021-01-26 Chemoprotective antimalarials identified through quantitative high-throughput screening of Plasmodium blood and liver stage parasites Dorjsuren, Dorjbal Eastman, Richard T. Wicht, Kathryn J. Jansen, Daniel Talley, Daniel C. Sigmon, Benjamin A. Zakharov, Alexey V. Roncal, Norma Girvin, Andrew T. Antonova-Koch, Yevgeniya Will, Paul M. Shah, Pranav Sun, Hongmao Klumpp-Thomas, Carleen Mok, Sachel Yeo, Tomas Meister, Stephan Marugan, Juan Jose Ross, Leila S. Xu, Xin Maloney, David J. Jadhav, Ajit Mott, Bryan T. Sciotti, Richard J. Winzeler, Elizabeth A. Waters, Norman C. Campbell, Robert F. Huang, Wenwei Simeonov, Anton Fidock, David A. Sci Rep Article The spread of Plasmodium falciparum parasites resistant to most first-line antimalarials creates an imperative to enrich the drug discovery pipeline, preferably with curative compounds that can also act prophylactically. We report a phenotypic quantitative high-throughput screen (qHTS), based on concentration–response curves, which was designed to identify compounds active against Plasmodium liver and asexual blood stage parasites. Our qHTS screened over 450,000 compounds, tested across a range of 5 to 11 concentrations, for activity against Plasmodium falciparum asexual blood stages. Active compounds were then filtered for unique structures and drug-like properties and subsequently screened in a P. berghei liver stage assay to identify novel dual-active antiplasmodial chemotypes. Hits from thiadiazine and pyrimidine azepine chemotypes were subsequently prioritized for resistance selection studies, yielding distinct mutations in P. falciparum cytochrome b, a validated antimalarial drug target. The thiadiazine chemotype was subjected to an initial medicinal chemistry campaign, yielding a metabolically stable analog with sub-micromolar potency. Our qHTS methodology and resulting dataset provides a large-scale resource to investigate Plasmodium liver and asexual blood stage parasite biology and inform further research to develop novel chemotypes as causal prophylactic antimalarials. Nature Publishing Group UK 2021-01-22 /pmc/articles/PMC7822874/ /pubmed/33483532 http://dx.doi.org/10.1038/s41598-021-81486-z Text en © The Author(s) 2021 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 licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence 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 licence, visit http://creativecommons.org/licenses/by/4.0/. |
spellingShingle | Article Dorjsuren, Dorjbal Eastman, Richard T. Wicht, Kathryn J. Jansen, Daniel Talley, Daniel C. Sigmon, Benjamin A. Zakharov, Alexey V. Roncal, Norma Girvin, Andrew T. Antonova-Koch, Yevgeniya Will, Paul M. Shah, Pranav Sun, Hongmao Klumpp-Thomas, Carleen Mok, Sachel Yeo, Tomas Meister, Stephan Marugan, Juan Jose Ross, Leila S. Xu, Xin Maloney, David J. Jadhav, Ajit Mott, Bryan T. Sciotti, Richard J. Winzeler, Elizabeth A. Waters, Norman C. Campbell, Robert F. Huang, Wenwei Simeonov, Anton Fidock, David A. Chemoprotective antimalarials identified through quantitative high-throughput screening of Plasmodium blood and liver stage parasites |
title | Chemoprotective antimalarials identified through quantitative high-throughput screening of Plasmodium blood and liver stage parasites |
title_full | Chemoprotective antimalarials identified through quantitative high-throughput screening of Plasmodium blood and liver stage parasites |
title_fullStr | Chemoprotective antimalarials identified through quantitative high-throughput screening of Plasmodium blood and liver stage parasites |
title_full_unstemmed | Chemoprotective antimalarials identified through quantitative high-throughput screening of Plasmodium blood and liver stage parasites |
title_short | Chemoprotective antimalarials identified through quantitative high-throughput screening of Plasmodium blood and liver stage parasites |
title_sort | chemoprotective antimalarials identified through quantitative high-throughput screening of plasmodium blood and liver stage parasites |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7822874/ https://www.ncbi.nlm.nih.gov/pubmed/33483532 http://dx.doi.org/10.1038/s41598-021-81486-z |
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