Journal article
Probing the distinct chemosensitivity of Plasmodium vivax liver stage parasites and demonstration of 8-aminoquinoline radical cure activity in vitro
- Abstract:
- Improved control of Plasmodium vivax malaria can be achieved with the discovery of new antimalarials with radical cure efficacy, including prevention of relapse caused by hypnozoites residing in the liver of patients. We screened several compound libraries against P. vivax liver stages, including 1565 compounds against mature hypnozoites, resulting in one drug-like and several probe-like hits useful for investigating hypnozoite biology. Primaquine and tafenoquine, administered in combination with chloroquine, are currently the only FDA-approved antimalarials for radical cure, yet their activity against mature P. vivax hypnozoites has not yet been demonstrated in vitro. By developing an extended assay, we show both drugs are individually hypnozonticidal and made more potent when partnered with chloroquine, similar to clinically relevant combinations. Post-hoc analyses of screening data revealed excellent performance of ionophore controls and the high quality of single point assays, demonstrating a platform able to support screening of greater compound numbers. A comparison of P. vivax liver stage activity data with that of the P. cynomolgi blood, P. falciparum blood, and P. berghei liver stages reveals overlap in schizonticidal but not hypnozonticidal activity, indicating that the delivery of new radical curative agents killing P. vivax hypnozoites requires an independent and focused drug development test cascade.
- Publication status:
- Published
- Peer review status:
- Peer reviewed
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(Preview, Version of record, 6.2MB, Terms of use)
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- Publisher copy:
- 10.1038/s41598-021-99152-9
Authors
- Publisher:
- Springer Nature
- Journal:
- Scientific Reports More from this journal
- Volume:
- 11
- Article number:
- 19905
- Place of publication:
- England
- Publication date:
- 2021-10-07
- Acceptance date:
- 2021-09-21
- DOI:
- EISSN:
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2045-2322
- Pmid:
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34620901
- Language:
-
English
- Keywords:
- Pubs id:
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1199713
- Local pid:
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pubs:1199713
- Deposit date:
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2021-12-22
Terms of use
- Copyright holder:
- Maher et al.
- Copyright date:
- 2021
- Rights statement:
- ©2021 The Author(s). Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
- Licence:
- CC Attribution (CC BY)
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