Journal article
Open-source discovery of chemical leads for next-generation chemoprotective antimalarials.
- 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.
- Publication status:
- Published
- Peer review status:
- Peer reviewed
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(Preview, Version of record, pdf, 3.2MB, Terms of use)
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- Publisher copy:
- 10.1126/science.aat9446
Authors
- Publisher:
- American Association for the Advancement of Science
- Journal:
- Science More from this journal
- Volume:
- 362
- Issue:
- 6419
- Pages:
- eaat9446
- Publication date:
- 2018-12-07
- Acceptance date:
- 2018-10-18
- DOI:
- EISSN:
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1095-9203
- ISSN:
-
0036-8075
- Pmid:
-
30523084
- Language:
-
English
- Keywords:
- Pubs id:
-
pubs:951531
- UUID:
-
uuid:d9357649-0500-41bb-af26-c8aa7cbfd2eb
- Local pid:
-
pubs:951531
- Source identifiers:
-
951531
- Deposit date:
-
2018-12-17
Terms of use
- Copyright holder:
- Antonova-Koch et al
- Copyright date:
- 2018
- Notes:
- Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
- Licence:
- CC Attribution (CC BY)
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