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

12 Citations (Scopus)

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

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Antimalarials
Plasmodium
Parasitemia
Chemoprevention
Luciferases
Malaria
Cluster Analysis
Parasites
Liver
In Vitro Techniques

All Science Journal Classification (ASJC) codes

  • General

Cite this

Antonova-Koch, Y., Meister, S., Abraham, M., Luth, M. R., Ottilie, S., Lukens, A. K., ... 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
Antonova-Koch, Yevgeniya ; Meister, Stephan ; Abraham, Matthew ; Luth, Madeline R. ; Ottilie, Sabine ; Lukens, Amanda K. ; Sakata-Kato, Tomoyo ; Vanaerschot, Manu ; Owen, Edward ; Jado Rodriguez, Juan Carlos ; Maher, Steven P. ; Calla, Jaeson ; Plouffe, David ; Zhong, Yang ; Chen, Kaisheng ; Chaumeau, Victor ; Conway, Amy J. ; McNamara, Case W. ; Ibanez, Maureen ; Gagaring, Kerstin ; Serrano, Fernando Neria ; Eribez, Korina ; Taggard, Cullin Mc Lean ; Cheung, Andrea L. ; Lincoln, Christie ; Ambachew, Biniam ; Rouillier, Melanie ; Siegel, Dionicio ; Nosten, François ; Kyle, Dennis E. ; Gamo, Francisco Javier ; Zhou, Yingyao ; Llinás, Manuel ; Fidock, David A. ; Wirth, Dyann F. ; Burrows, Jeremy ; Campo, Brice ; Winzeler, Elizabeth A. / Open-source discovery of chemical leads for next-generation chemoprotective antimalarials. In: Science. 2018 ; Vol. 362, No. 6419.
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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.",
author = "Yevgeniya Antonova-Koch and Stephan Meister and Matthew Abraham and Luth, {Madeline R.} and Sabine Ottilie and Lukens, {Amanda K.} and Tomoyo Sakata-Kato and Manu Vanaerschot and Edward Owen and {Jado Rodriguez}, {Juan Carlos} and Maher, {Steven P.} and Jaeson Calla and David Plouffe and Yang Zhong and Kaisheng Chen and Victor Chaumeau and Conway, {Amy J.} and McNamara, {Case W.} and Maureen Ibanez and Kerstin Gagaring and Serrano, {Fernando Neria} and Korina Eribez and Taggard, {Cullin Mc Lean} and Cheung, {Andrea L.} and Christie Lincoln and Biniam Ambachew and Melanie Rouillier and Dionicio Siegel and Fran{\cc}ois Nosten and Kyle, {Dennis E.} and Gamo, {Francisco Javier} and Yingyao Zhou and Manuel Llin{\'a}s and Fidock, {David A.} and Wirth, {Dyann F.} and Jeremy Burrows and Brice Campo and Winzeler, {Elizabeth A.}",
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Antonova-Koch, Y, Meister, S, Abraham, M, Luth, MR, Ottilie, S, Lukens, AK, Sakata-Kato, T, Vanaerschot, M, Owen, E, Jado Rodriguez, JC, Maher, SP, Calla, J, Plouffe, D, Zhong, Y, Chen, K, Chaumeau, V, Conway, AJ, McNamara, CW, Ibanez, M, Gagaring, K, Serrano, FN, Eribez, K, Taggard, CML, Cheung, AL, Lincoln, C, Ambachew, B, Rouillier, M, Siegel, D, Nosten, F, Kyle, DE, Gamo, FJ, Zhou, Y, Llinás, M, Fidock, DA, Wirth, DF, Burrows, J, Campo, B & Winzeler, EA 2018, 'Open-source discovery of chemical leads for next-generation chemoprotective antimalarials', Science, vol. 362, no. 6419, eaat9446. https://doi.org/10.1126/science.aat9446

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

In: Science, Vol. 362, No. 6419, eaat9446, 07.12.2018.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Open-source discovery of chemical leads for next-generation chemoprotective antimalarials

AU - Antonova-Koch, Yevgeniya

AU - Meister, Stephan

AU - Abraham, Matthew

AU - Luth, Madeline R.

AU - Ottilie, Sabine

AU - Lukens, Amanda K.

AU - Sakata-Kato, Tomoyo

AU - Vanaerschot, Manu

AU - Owen, Edward

AU - Jado Rodriguez, Juan Carlos

AU - Maher, Steven P.

AU - Calla, Jaeson

AU - Plouffe, David

AU - Zhong, Yang

AU - Chen, Kaisheng

AU - Chaumeau, Victor

AU - Conway, Amy J.

AU - McNamara, Case W.

AU - Ibanez, Maureen

AU - Gagaring, Kerstin

AU - Serrano, Fernando Neria

AU - Eribez, Korina

AU - Taggard, Cullin Mc Lean

AU - Cheung, Andrea L.

AU - Lincoln, Christie

AU - Ambachew, Biniam

AU - Rouillier, Melanie

AU - Siegel, Dionicio

AU - Nosten, François

AU - Kyle, Dennis E.

AU - Gamo, Francisco Javier

AU - Zhou, Yingyao

AU - Llinás, Manuel

AU - Fidock, David A.

AU - Wirth, Dyann F.

AU - Burrows, Jeremy

AU - Campo, Brice

AU - Winzeler, Elizabeth A.

PY - 2018/12/7

Y1 - 2018/12/7

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Antonova-Koch Y, Meister S, Abraham M, Luth MR, Ottilie S, Lukens AK et al. Open-source discovery of chemical leads for next-generation chemoprotective antimalarials. Science. 2018 Dec 7;362(6419). eaat9446. https://doi.org/10.1126/science.aat9446