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Open-source discovery of chemical leads for next-generation chemoprotective antimalarials.


ABSTRACT: To discover leads for next-generation chemoprotective antimalarial drugs, we tested more than 500,000 compounds for their ability to inhibit liver-stage development of luciferase-expressing Plasmodium spp. parasites (681 compounds showed a half-maximal inhibitory concentration of less than 1 micromolar). Cluster analysis identified potent and previously unreported scaffold families as well as other series previously associated with chemoprophylaxis. Further testing through multiple phenotypic assays that predict stage-specific and multispecies antimalarial activity distinguished compound classes that are likely to provide symptomatic relief by reducing asexual blood-stage parasitemia from those which are likely to only prevent malaria. Target identification by using functional assays, in vitro evolution, or metabolic profiling revealed 58 mitochondrial inhibitors but also many chemotypes possibly with previously unidentified mechanisms of action.

SUBMITTER: Antonova-Koch Y 

PROVIDER: S-EPMC6516198 | biostudies-literature | 2018 Dec

REPOSITORIES: biostudies-literature

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Open-source discovery of chemical leads for next-generation chemoprotective antimalarials.

Antonova-Koch Yevgeniya Y   Meister Stephan S   Abraham Matthew M   Luth Madeline R MR   Ottilie Sabine S   Lukens Amanda K AK   Sakata-Kato Tomoyo T   Vanaerschot Manu M   Owen Edward E   Jado Juan Carlos JC   Maher Steven P SP   Calla Jaeson J   Plouffe David D   Zhong Yang Y   Chen Kaisheng K   Chaumeau Victor V   Conway Amy J AJ   McNamara Case W CW   Ibanez Maureen M   Gagaring Kerstin K   Serrano Fernando Neria FN   Eribez Korina K   Taggard Cullin McLean CM   Cheung Andrea L AL   Lincoln Christie C   Ambachew Biniam B   Rouillier Melanie M   Siegel Dionicio D   Nosten François F   Kyle Dennis E DE   Gamo Francisco-Javier FJ   Zhou Yingyao Y   Llinás Manuel M   Fidock David A DA   Wirth Dyann F DF   Burrows Jeremy J   Campo Brice B   Winzeler Elizabeth A EA  

Science (New York, N.Y.) 20181201 6419


To discover leads for next-generation chemoprotective antimalarial drugs, we tested more than 500,000 compounds for their ability to inhibit liver-stage development of luciferase-expressing <i>Plasmodium</i> spp. parasites (681 compounds showed a half-maximal inhibitory concentration of less than 1 micromolar). Cluster analysis identified potent and previously unreported scaffold families as well as other series previously associated with chemoprophylaxis. Further testing through multiple phenot  ...[more]

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