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.
N1 - Funding Information:
We thank A. Rodriguez and the New York University for providing P. berghei–infected mosquitoes, the Pennsylvania State University Metabolomics Core Facility (University Park, Pennsylvania) for critical analytical expertise, and H. Painter for valuable input on the metabolomics experimental setup. We also thank G. LaMonte for assistance with parasite culture and P. Hinkson (Harvard Chan School) for technical support, and we thank S. Mikolajczak (Center for Infectious Disease Research) for the PvUIS4 antibodies. DNA sequencing was performed at the University of California, San Diego (UCSD), with support from the Institute of Genomic Medicine Core. The red blood cells used in this work were sourced ethically, and their research use was in accord with the terms of the informed consents. The compound library was acquired from Charles River. We thank the Shoklo Malaria Research Unit staff involved in this study, especially P. Kittiphanakun, S. N. Hsel, N. Keereepitoon, and S. Saithanmettajit for their help in mosquito rearing and P. vivax infection. Funding: E.A.W. is supported by grants from the NIH (5R01AI090141, R01AI103058, and P50GM085764) and by grants from the Bill & Melinda Gates Foundation (OPP1086217 and OPP1141300) as well as from Medicines for Malaria Venture (MMV). M.L.L. received support from Bill & Melinda Gates Foundation Phase II Grand Challenges (OPP1119049). This work was also funded in part by National Institutes of Health grant R01AI093716 supporting D.F.W., A.K.L., and T.S.K.; D.E.K. and S.P.M. are supported by grants from the Bill & Melinda Gates Foundation (OPP1023601), the Georgia Research Alliance, and the Medicines for Malaria Venture (RD/15/ 0022). The Human Subjects protocol for the P. vivax study was approved by the Oxford Tropical Medicine Ethical Committee, Oxford University, England (TMEC 14-016 and OxTREC 40-14). The Shoklo Malaria Research Unit is part of the Mahidol Oxford Research Unit, supported by the Wellcome Trust of Great Britain. The Human Subjects protocol for the UCSD P. falciparum study was approved by The Scripps Research Institute Institutional Review Board as part of the Normal Blood Donor Service.
Publisher Copyright:
© 2017 The Authors, some rights reserved
PY - 2018/12/7
Y1 - 2018/12/7
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85057744039&partnerID=8YFLogxK
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U2 - 10.1126/science.aat9446
DO - 10.1126/science.aat9446
M3 - Article
C2 - 30523084
AN - SCOPUS:85057744039
SN - 0036-8075
VL - 362
JO - Science
JF - Science
IS - 6419
M1 - eaat9446
ER -