Chemoprotective antimalarials identified through quantitative high-throughput screening of Plasmodium blood and liver stage parasites

Abstract 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), bas...

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Autores principales:	Dorjbal Dorjsuren, Richard T. Eastman, Kathryn J. Wicht, Daniel Jansen, Daniel C. Talley, Benjamin A. Sigmon, Alexey V. Zakharov, Norma Roncal, Andrew T. Girvin, Yevgeniya Antonova-Koch, Paul M. Will, Pranav Shah, Hongmao Sun, Carleen Klumpp-Thomas, Sachel Mok, Tomas Yeo, Stephan Meister, Juan Jose Marugan, Leila S. Ross, Xin Xu, David J. Maloney, Ajit Jadhav, Bryan T. Mott, Richard J. Sciotti, Elizabeth A. Winzeler, Norman C. Waters, Robert F. Campbell, Wenwei Huang, Anton Simeonov, David A. Fidock
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/3166e3dd3b5945e88b4f3c4eb22c8065
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spelling	oai:doaj.org-article:3166e3dd3b5945e88b4f3c4eb22c80652021-12-02T13:48:53ZChemoprotective antimalarials identified through quantitative high-throughput screening of Plasmodium blood and liver stage parasites10.1038/s41598-021-81486-z2045-2322https://doaj.org/article/3166e3dd3b5945e88b4f3c4eb22c80652021-01-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-81486-zhttps://doaj.org/toc/2045-2322Abstract 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.Dorjbal DorjsurenRichard T. EastmanKathryn J. WichtDaniel JansenDaniel C. TalleyBenjamin A. SigmonAlexey V. ZakharovNorma RoncalAndrew T. GirvinYevgeniya Antonova-KochPaul M. WillPranav ShahHongmao SunCarleen Klumpp-ThomasSachel MokTomas YeoStephan MeisterJuan Jose MaruganLeila S. RossXin XuDavid J. MaloneyAjit JadhavBryan T. MottRichard J. SciottiElizabeth A. WinzelerNorman C. WatersRobert F. CampbellWenwei HuangAnton SimeonovDavid A. FidockNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-16 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Dorjbal Dorjsuren Richard T. Eastman Kathryn J. Wicht Daniel Jansen Daniel C. Talley Benjamin A. Sigmon Alexey V. Zakharov Norma Roncal Andrew T. Girvin Yevgeniya Antonova-Koch Paul M. Will Pranav Shah Hongmao Sun Carleen Klumpp-Thomas Sachel Mok Tomas Yeo Stephan Meister Juan Jose Marugan Leila S. Ross Xin Xu David J. Maloney Ajit Jadhav Bryan T. Mott Richard J. Sciotti Elizabeth A. Winzeler Norman C. Waters Robert F. Campbell Wenwei Huang Anton Simeonov David A. Fidock Chemoprotective antimalarials identified through quantitative high-throughput screening of Plasmodium blood and liver stage parasites
description	Abstract 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	article
author	Dorjbal Dorjsuren Richard T. Eastman Kathryn J. Wicht Daniel Jansen Daniel C. Talley Benjamin A. Sigmon Alexey V. Zakharov Norma Roncal Andrew T. Girvin Yevgeniya Antonova-Koch Paul M. Will Pranav Shah Hongmao Sun Carleen Klumpp-Thomas Sachel Mok Tomas Yeo Stephan Meister Juan Jose Marugan Leila S. Ross Xin Xu David J. Maloney Ajit Jadhav Bryan T. Mott Richard J. Sciotti Elizabeth A. Winzeler Norman C. Waters Robert F. Campbell Wenwei Huang Anton Simeonov David A. Fidock
author_facet	Dorjbal Dorjsuren Richard T. Eastman Kathryn J. Wicht Daniel Jansen Daniel C. Talley Benjamin A. Sigmon Alexey V. Zakharov Norma Roncal Andrew T. Girvin Yevgeniya Antonova-Koch Paul M. Will Pranav Shah Hongmao Sun Carleen Klumpp-Thomas Sachel Mok Tomas Yeo Stephan Meister Juan Jose Marugan Leila S. Ross Xin Xu David J. Maloney Ajit Jadhav Bryan T. Mott Richard J. Sciotti Elizabeth A. Winzeler Norman C. Waters Robert F. Campbell Wenwei Huang Anton Simeonov David A. Fidock
author_sort	Dorjbal Dorjsuren
title	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_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_sort	chemoprotective antimalarials identified through quantitative high-throughput screening of plasmodium blood and liver stage parasites
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/3166e3dd3b5945e88b4f3c4eb22c8065
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Chemoprotective antimalarials identified through quantitative high-throughput screening of Plasmodium blood and liver stage parasites

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