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

Yevgeniya Antonova-Koch, Stephan Meister, Matthew Abraham, Madeline R. Luth, Sabine Ottilie, Amanda K. Lukens, Tomoyo Sakata-Kato, Manu Vanaerschot, Edward Owen, Juan Carlos Jado Rodriguez, Steven P. Maher, Jaeson Calla, David Plouffe, Yang Zhong, Kaisheng Chen, Victor Chaumeau, Amy J. Conway, Case W. McNamara, Maureen Ibanez, Kerstin GagaringFernando Neria Serrano, Korina Eribez, Cullin Mc Lean Taggard, Andrea L. Cheung, Christie Lincoln, Biniam Ambachew, Melanie Rouillier, Dionicio Siegel, François Nosten, Dennis E. Kyle, Francisco Javier Gamo, Yingyao Zhou, Manuel Llinás, David A. Fidock, Dyann F. Wirth, Jeremy Burrows, Brice Campo, Elizabeth A. Winzeler

Research output: Contribution to journalArticle

22 Scopus citations

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.

Original languageEnglish (US)
Article numbereaat9446
JournalScience
Volume362
Issue number6419
DOIs
StatePublished - Dec 7 2018

All Science Journal Classification (ASJC) codes

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    Antonova-Koch, Y., Meister, S., Abraham, M., Luth, M. R., Ottilie, S., Lukens, A. K., Sakata-Kato, T., Vanaerschot, M., Owen, E., Jado Rodriguez, J. C., Maher, S. P., Calla, J., Plouffe, D., Zhong, Y., Chen, K., Chaumeau, V., Conway, A. J., McNamara, C. W., Ibanez, M., ... Winzeler, E. A. (2018). Open-source discovery of chemical leads for next-generation chemoprotective antimalarials. Science, 362(6419), [eaat9446]. https://doi.org/10.1126/science.aat9446