A novel 4-aminoquinoline chemotype with multistage antimalarial activity and lack of cross-resistance with PfCRT and PfMDR1 mutants
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| Publication Date: | 2024 |
| Other Authors: | , , , , , , , , , , , , , , , |
| Format: | Article |
| Language: | eng |
| Source: | Repositórios Científicos de Acesso Aberto de Portugal (RCAAP) |
| Download full: | http://hdl.handle.net/10362/180598 |
Summary: | Funding Information: This 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). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Publisher Copyright: Copyright: © 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. |
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A novel 4-aminoquinoline chemotype with multistage antimalarial activity and lack of cross-resistance with PfCRT and PfMDR1 mutantsParasitologyMicrobiologyImmunologyMolecular BiologyGeneticsVirologySDG 3 - Good Health and Well-beingFunding Information: This 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). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Publisher Copyright: Copyright: © 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.Artemisinin-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.Laboratório Associado de Translacção e Inovação para a Saúde Global - LA Real (Pólo IHMT)Vector borne diseases and pathogens (VBD)Global Health and Tropical Medicine (GHTM)Instituto de Higiene e Medicina Tropical (IHMT)RUNFerreira, Letícia TiburcioCassiano, Gustavo CapattiAlvarez, Luis Carlos SalazarOkombo, JohnCalit, JulianaFontinha, DianaGil-Iturbe, EvaCoyle, RachaelAndrade, Carolina HortaSunnerhagen, PerBargieri, Daniel YoussefPrudêncio, MiguelQuick, MatthiasCravo, Pedro V.Lee, Marcus C. S.Fidock, David A.Costa, Fabio Trindade Maranhão2025-03-13T21:15:07Z2024-10-292024-10-29T00:00:00Zinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/article25application/pdfhttp://hdl.handle.net/10362/180598eng1553-7366PURE: 112587912https://doi.org/10.1371/journal.ppat.1012627info:eu-repo/semantics/openAccessreponame:Repositórios Científicos de Acesso Aberto de Portugal (RCAAP)instname:FCCN, serviços digitais da FCT – Fundação para a Ciência e a Tecnologiainstacron:RCAAP2025-03-31T01:59:42Zoai:run.unl.pt:10362/180598Portal AgregadorONGhttps://www.rcaap.pt/oai/openaireinfo@rcaap.ptopendoar:https://opendoar.ac.uk/repository/71602025-05-29T04:41:58.644508Repositórios Científicos de Acesso Aberto de Portugal (RCAAP) - FCCN, serviços digitais da FCT – Fundação para a Ciência e a Tecnologiafalse |
| dc.title.none.fl_str_mv |
A novel 4-aminoquinoline chemotype with multistage antimalarial activity and lack of cross-resistance with PfCRT and PfMDR1 mutants |
| title |
A novel 4-aminoquinoline chemotype with multistage antimalarial activity and lack of cross-resistance with PfCRT and PfMDR1 mutants |
| spellingShingle |
A novel 4-aminoquinoline chemotype with multistage antimalarial activity and lack of cross-resistance with PfCRT and PfMDR1 mutants Ferreira, Letícia Tiburcio Parasitology Microbiology Immunology Molecular Biology Genetics Virology SDG 3 - Good Health and Well-being |
| title_short |
A novel 4-aminoquinoline chemotype with multistage antimalarial activity and lack of cross-resistance with PfCRT and PfMDR1 mutants |
| title_full |
A novel 4-aminoquinoline chemotype with multistage antimalarial activity and lack of cross-resistance with PfCRT and PfMDR1 mutants |
| title_fullStr |
A novel 4-aminoquinoline chemotype with multistage antimalarial activity and lack of cross-resistance with PfCRT and PfMDR1 mutants |
| title_full_unstemmed |
A novel 4-aminoquinoline chemotype with multistage antimalarial activity and lack of cross-resistance with PfCRT and PfMDR1 mutants |
| title_sort |
A novel 4-aminoquinoline chemotype with multistage antimalarial activity and lack of cross-resistance with PfCRT and PfMDR1 mutants |
| author |
Ferreira, Letícia Tiburcio |
| author_facet |
Ferreira, Letícia Tiburcio Cassiano, Gustavo Capatti Alvarez, Luis Carlos Salazar Okombo, John Calit, Juliana Fontinha, Diana Gil-Iturbe, Eva Coyle, Rachael Andrade, Carolina Horta Sunnerhagen, Per Bargieri, Daniel Youssef Prudêncio, Miguel Quick, Matthias Cravo, Pedro V. Lee, Marcus C. S. Fidock, David A. Costa, Fabio Trindade Maranhão |
| author_role |
author |
| author2 |
Cassiano, Gustavo Capatti Alvarez, Luis Carlos Salazar Okombo, John Calit, Juliana Fontinha, Diana Gil-Iturbe, Eva Coyle, Rachael Andrade, Carolina Horta Sunnerhagen, Per Bargieri, Daniel Youssef Prudêncio, Miguel Quick, Matthias Cravo, Pedro V. Lee, Marcus C. S. Fidock, David A. Costa, Fabio Trindade Maranhão |
| author2_role |
author author author author author author author author author author author author author author author author |
| dc.contributor.none.fl_str_mv |
Laboratório Associado de Translacção e Inovação para a Saúde Global - LA Real (Pólo IHMT) Vector borne diseases and pathogens (VBD) Global Health and Tropical Medicine (GHTM) Instituto de Higiene e Medicina Tropical (IHMT) RUN |
| dc.contributor.author.fl_str_mv |
Ferreira, Letícia Tiburcio Cassiano, Gustavo Capatti Alvarez, Luis Carlos Salazar Okombo, John Calit, Juliana Fontinha, Diana Gil-Iturbe, Eva Coyle, Rachael Andrade, Carolina Horta Sunnerhagen, Per Bargieri, Daniel Youssef Prudêncio, Miguel Quick, Matthias Cravo, Pedro V. Lee, Marcus C. S. Fidock, David A. Costa, Fabio Trindade Maranhão |
| dc.subject.por.fl_str_mv |
Parasitology Microbiology Immunology Molecular Biology Genetics Virology SDG 3 - Good Health and Well-being |
| topic |
Parasitology Microbiology Immunology Molecular Biology Genetics Virology SDG 3 - Good Health and Well-being |
| description |
Funding Information: This 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). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Publisher Copyright: Copyright: © 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. |
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2024 |
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2024-10-29 2024-10-29T00:00:00Z 2025-03-13T21:15:07Z |
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1553-7366 PURE: 112587912 https://doi.org/10.1371/journal.ppat.1012627 |
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