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Title: Open-source discovery of chemical leads for next-generation chemoprotective antimalarials
Authors: 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 Gagaring
Fernando 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
GlaxoSmithKline plc, Spain
Harvard School of Public Health
University of California, San Diego
The University of Georgia
Columbia University Medical Center
University of California, San Diego, School of Medicine
Mahidol University
The Genomics Institute of the Novartis Research Foundation
Nuffield Department of Clinical Medicine
University of South Florida, Tampa
Pennsylvania State University
Broad Institute
California Institute for Biomedical Research
Medicines for Malaria Venture
Keywords: Multidisciplinary
Issue Date: 7-Dec-2018
Citation: Science. Vol.362, No.6419 (2018)
Abstract: © 2017 The Authors, some rights reserved 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.
ISSN: 10959203
Appears in Collections:Scopus 2018

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