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

Issued Date

2018-12-07

Resource Type

Article

ISSN

10959203
00368075

DOI

10.1126/science.aat9446

Other identifier(s)

2-s2.0-85057744039

Rights

Mahidol University

Rights Holder(s)

SCOPUS

Bibliographic Citation

Science. Vol.362, No.6419 (2018)

Suggested Citation

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 Open-source discovery of chemical leads for next-generation chemoprotective antimalarials. Science. Vol.362, No.6419 (2018). doi:10.1126/science.aat9446 Retrieved from: https://repository.li.mahidol.ac.th/handle/20.500.14594/47459

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Title

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

Author(s)

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

Other Contributor(s)

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
 BioSero
 California Institute for Biomedical Research
 Medicines for Malaria Venture

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.

Keyword(s)

Multidisciplinary

Availability

URI

https://repository.li.mahidol.ac.th/handle/20.500.14594/47459

Collections

Scopus 2018