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 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.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2021 |
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| Erschienen: |
2021 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:11 |
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| Enthalten in: |
Scientific reports - 11(2021), 1 vom: 22. Jan., Seite 2121 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Dorjsuren, Dorjbal [VerfasserIn] |
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| Links: |
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| Themen: |
Antimalarials |
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| Anmerkungen: |
Date Completed 20.09.2021 Date Revised 20.09.2021 published: Electronic Citation Status MEDLINE |
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| doi: |
10.1038/s41598-021-81486-z |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM320457494 |
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| 500 | |a Citation Status MEDLINE | ||
| 520 | |a 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 | ||
| 650 | 4 | |a Journal Article | |
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| 650 | 7 | |a Protective Agents |2 NLM | |
| 650 | 7 | |a Thiadiazines |2 NLM | |
| 700 | 1 | |a Eastman, Richard T |e verfasserin |4 aut | |
| 700 | 1 | |a Wicht, Kathryn J |e verfasserin |4 aut | |
| 700 | 1 | |a Jansen, Daniel |e verfasserin |4 aut | |
| 700 | 1 | |a Talley, Daniel C |e verfasserin |4 aut | |
| 700 | 1 | |a Sigmon, Benjamin A |e verfasserin |4 aut | |
| 700 | 1 | |a Zakharov, Alexey V |e verfasserin |4 aut | |
| 700 | 1 | |a Roncal, Norma |e verfasserin |4 aut | |
| 700 | 1 | |a Girvin, Andrew T |e verfasserin |4 aut | |
| 700 | 1 | |a Antonova-Koch, Yevgeniya |e verfasserin |4 aut | |
| 700 | 1 | |a Will, Paul M |e verfasserin |4 aut | |
| 700 | 1 | |a Shah, Pranav |e verfasserin |4 aut | |
| 700 | 1 | |a Sun, Hongmao |e verfasserin |4 aut | |
| 700 | 1 | |a Klumpp-Thomas, Carleen |e verfasserin |4 aut | |
| 700 | 1 | |a Mok, Sachel |e verfasserin |4 aut | |
| 700 | 1 | |a Yeo, Tomas |e verfasserin |4 aut | |
| 700 | 1 | |a Meister, Stephan |e verfasserin |4 aut | |
| 700 | 1 | |a Marugan, Juan Jose |e verfasserin |4 aut | |
| 700 | 1 | |a Ross, Leila S |e verfasserin |4 aut | |
| 700 | 1 | |a Xu, Xin |e verfasserin |4 aut | |
| 700 | 1 | |a Maloney, David J |e verfasserin |4 aut | |
| 700 | 1 | |a Jadhav, Ajit |e verfasserin |4 aut | |
| 700 | 1 | |a Mott, Bryan T |e verfasserin |4 aut | |
| 700 | 1 | |a Sciotti, Richard J |e verfasserin |4 aut | |
| 700 | 1 | |a Winzeler, Elizabeth A |e verfasserin |4 aut | |
| 700 | 1 | |a Waters, Norman C |e verfasserin |4 aut | |
| 700 | 1 | |a Campbell, Robert F |e verfasserin |4 aut | |
| 700 | 1 | |a Huang, Wenwei |e verfasserin |4 aut | |
| 700 | 1 | |a Simeonov, Anton |e verfasserin |4 aut | |
| 700 | 1 | |a Fidock, David A |e verfasserin |4 aut | |
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