Repository logo
 
Publication

A novel 4-aminoquinoline chemotype with multistage antimalarial activity and lack of cross-resistance with PfCRT and PfMDR1 mutants

2024Journal article Open access
Simple item page
dc.contributor.authorFerreira, Letícia Tiburcio
dc.contributor.authorCassiano, Gustavo Capatti
dc.contributor.authorAlvarez, Luis Carlos Salazar
dc.contributor.authorOkombo, John
dc.contributor.authorCalit, Juliana
dc.contributor.authorFontinha, Diana
dc.contributor.authorGil-Iturbe, Eva
dc.contributor.authorCoyle, Rachael
dc.contributor.authorAndrade, Carolina Horta
dc.contributor.authorSunnerhagen, Per
dc.contributor.authorBargieri, Daniel Youssef
dc.contributor.authorPrudêncio, Miguel
dc.contributor.authorQuick, Matthias
dc.contributor.authorCravo, Pedro V.
dc.contributor.authorLee, Marcus C. S.
dc.contributor.authorFidock, David A.
dc.contributor.authorCosta, Fabio Trindade Maranhão
dc.date.accessioned2024-11-21T12:19:28Z
dc.date.available2024-11-21T12:19:28Z
dc.date.issued2024
dc.descriptionCopyright: © 2024 Ferreira et al. 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 author and source are credited.pt_PT
dc.description.abstractArtemisinin-based combination therapy (ACT) is the mainstay of effective treatment of Plasmodium falciparum malaria. However, the long-term utility of ACTs is imperiled by widespread partial artemisinin resistance in Southeast Asia and its recent emergence in parts of East Africa. This underscores the need to identify chemotypes with new modes of action (MoAs) to circumvent resistance to ACTs. In this study, we characterized the asexual blood stage antiplasmodial activity and resistance mechanisms of LDT-623, a 4-aminoquinoline (4-AQ). We also detected LDT-623 activity against multiple stages (liver schizonts, stage IV-V gametocytes, and ookinetes) of Plasmodium's life cycle, a feature unlike other 4-AQs such as chloroquine (CQ) and piperaquine (PPQ). Using heme fractionation profiling and drug uptake studies in PfCRT-containing proteoliposomes, we observed inhibition of hemozoin formation and PfCRT-mediated transport, which constitute characteristic features of 4-AQs' MoA. We also found minimal cross-resistance to LDT-623 in a panel of mutant pfcrt or pfmdr1 lines, but not the PfCRT F145I mutant that is highly resistant to PPQ resistance yet is very unfit. No P. falciparum parasites were recovered in an in vitro resistance selection study, suggesting a high barrier for resistance to emerge. Finally, a competitive growth assay comprising >50 barcoded parasite lines with mutated resistance mediators or major drug targets found no evidence of cross-resistance. Our findings support further exploration of this promising 4-AQ.pt_PT
dc.description.sponsorshipThis study was supported by Fundação de Amparo à Pesquisa do Estado de São Paulo - FAPESP (2019/02171-3 and 2021/13809-9 to LTF, 2017/18611-7 to FTMC, 2021/06769-0 to DYB, and 2018/24878-9 to JC), Conselho Nacional de Desenvolvimento Científico e Tecnológico – CNPq (441038/2020-4 and 440373/2022-0 to CHA, and 162117/2018-3 to LCSA), and the National Institutes of Health – NIH (R01 AI124678 and R37 AI050234 to DAF, R01 AI147628 to MQ, DAF). CHA was also supported by Fundação de Amparo à Pesquisa do Estado de Goiás (202010267000272). DYB acknowledges funding from Instituto Serrapilheira (G-1709-16618). MP is funded by “la Caixa” (HR21-848) and European Union Horizon Europe programme (101080744). PS was supported by the Swedish Research Council - Vetenskapsrådet (2021-03667) and The Swedish Foundation for International Cooperation in Research and Higher Education - STINT (BR2018-8017). MCSL gratefully acknowledges funding from the Bill and Melinda Gates Foundation (OPP1054480).pt_PT
dc.description.versioninfo:eu-repo/semantics/publishedVersionpt_PT
dc.identifier.citationPLoS Pathog. 2024 Oct 29;20(10):e1012627pt_PT
dc.identifier.doi10.1371/journal.ppat.1012627pt_PT
dc.identifier.eissn1553-7374
dc.identifier.issn1553-7366
dc.identifier.urihttp://hdl.handle.net/10400.5/95501
dc.language.isoengpt_PT
dc.peerreviewedyespt_PT
dc.publisherPLoSpt_PT
dc.relation101080744pt_PT
dc.relation.publisherversionhttps://journals.plos.org/plospathogens/pt_PT
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/pt_PT
dc.titleA novel 4-aminoquinoline chemotype with multistage antimalarial activity and lack of cross-resistance with PfCRT and PfMDR1 mutantspt_PT
dc.typejournal article
dspace.entity.typePublication
oaire.citation.issue10pt_PT
oaire.citation.titlePLOS Pathogenspt_PT
oaire.citation.volume20pt_PT
person.familyNameFontinha
person.familyNamePrudêncio
person.givenNameDiana
person.givenNameMiguel
person.identifierhttps://scholar.google.pt/citations?user=zduN6wsAAAAJ&hl=pt-PT&oi=ao
person.identifier.ciencia-id6A17-C404-F33B
person.identifier.ciencia-id5511-16ED-48E0
person.identifier.orcid0000-0002-0046-648X
person.identifier.orcid0000-0003-1746-6029
person.identifier.scopus-author-id6603561872
rcaap.rightsopenAccesspt_PT
rcaap.typearticlept_PT
relation.isAuthorOfPublication4fa5980c-148c-4e44-a818-9e8d09245891
relation.isAuthorOfPublication80e4e74d-bf34-4a71-8530-cc3280543b65
relation.isAuthorOfPublication.latestForDiscovery80e4e74d-bf34-4a71-8530-cc3280543b65

Files

Original bundle
Now showing 1 - 1 of 1
Thumbnail Image
Name:
A_novel4.pdf
Size:
2.85 MB
Format:
Adobe Portable Document Format
Download
License bundle
Now showing 1 - 1 of 1
No Thumbnail Available
Name:
license.txt
Size:
1.2 KB
Format:
Item-specific license agreed upon to submission
Description:
Download

Collections

IMM - Artigos em Revistas Internacionais
FM - Artigos em Revistas Internacionais