The protein aggregation inhibitor YAT2150 has potent antimalarial activity in Plasmodium falciparum in vitro cultures
Autor(a) principal: | |
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Data de Publicação: | 2022 |
Outros Autores: | , , , , , , , , , , |
Tipo de documento: | Artigo |
Idioma: | eng |
Título da fonte: | Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
Texto Completo: | http://hdl.handle.net/10451/54927 |
Resumo: | © The Author(s) 2022. 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/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. |
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The protein aggregation inhibitor YAT2150 has potent antimalarial activity in Plasmodium falciparum in vitro culturesAmyloid pan-inhibitorsAntimalarial drugsMalariaPlasmodium falciparumProtein aggregationYAT2150© The Author(s) 2022. 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/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.Background: By 2016, signs of emergence of Plasmodium falciparum resistance to artemisinin and partner drugs were detected in the Greater Mekong Subregion. Recently, the independent evolution of artemisinin resistance has also been reported in Africa and South America. This alarming scenario calls for the urgent development of new antimalarials with novel modes of action. We investigated the interference with protein aggregation, which is potentially toxic for the cell and occurs abundantly in all Plasmodium stages, as a hitherto unexplored drug target in the pathogen. Results: Attempts to exacerbate the P. falciparum proteome's propensity to aggregation by delivering endogenous aggregative peptides to in vitro cultures of this parasite did not significantly affect their growth. In contrast, protein aggregation inhibitors clearly reduced the pathogen's viability. One such compound, the bis(styrylpyridinium) salt YAT2150, exhibited potent antiplasmodial activity with an in vitro IC50 of 90 nM for chloroquine- and artemisinin-resistant lines, arresting asexual blood parasites at the trophozoite stage, as well as interfering with the development of both sexual and hepatic forms of Plasmodium. At its IC50, this compound is a powerful inhibitor of the aggregation of the model amyloid β peptide fragment 1-40, and it reduces the amount of aggregated proteins in P. falciparum cultures, suggesting that the underlying antimalarial mechanism consists in a generalized impairment of proteostasis in the pathogen. YAT2150 has an easy, rapid, and inexpensive synthesis, and because it fluoresces when it accumulates in its main localization in the Plasmodium cytosol, it is a theranostic agent. Conclusions: Inhibiting protein aggregation in Plasmodium significantly reduces the parasite's viability in vitro. Since YAT2150 belongs to a novel structural class of antiplasmodials with a mode of action that potentially targets multiple gene products, rapid evolution of resistance to this drug is unlikely to occur, making it a promising compound for the post-artemisinin era.This work was supported by grants (i) PCIN-2017-100, RTI2018-094579-B-I00 and PID2021-128325OB-I00 (XF-B), and SAF2017-82771-R and PID2020-118127RB-I00 (DM-T), funded by Ministerio de Ciencia e Innovación/Agencia Estatal de Investigación (MCIN/AEI/10.13039/501100011033 for grants PID2021- and PID2020-), which for grants RTI2018-, PID2021-, and SAF2017- included FEDER funds; (ii) ERA-NET Cofund EURONANOMED (http://euronanomed.net/), grant number 2017-178 (XF-B); and (iii) Generalitat de Catalunya, Spain (http://agaur.gencat.cat/), grant numbers 2017-SGR-908 (XF-B) and 2017-SGR-106 (DM-T). Work at Pompeu Fabra University was supported by the “La Caixa” Banking Foundation (https://fundacionlacaixa.org/, grant HR17-00409), and by grant AGL2017-84097-C2-2-R and the “María de Maeztu” Program for Units of Excellence in R&D from the Spanish Ministry of Science, Innovation and Universities.Springer NatureRepositório da Universidade de LisboaBouzón-Arnáiz, InésAvalos-Padilla, YunuenBiosca, ArnauCaño-Prades, OmarRomán-Álamo, LucíaValle, JavierAndreu, DavidMoita, DianaPrudêncio, MiguelArce, Elsa M.Muñoz-Torrero, DiegoFernàndez-Busquets, Xavier2022-10-26T15:40:40Z20222022-01-01T00:00:00Zinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articleapplication/pdfhttp://hdl.handle.net/10451/54927engBMC Biol. 2022 Oct 22;20(1):19710.1186/s12915-022-01374-41741-7007info:eu-repo/semantics/openAccessreponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãoinstacron:RCAAP2023-11-08T17:01:35Zoai:repositorio.ul.pt:10451/54927Portal AgregadorONGhttps://www.rcaap.pt/oai/openaireopendoar:71602024-03-19T22:05:39.544897Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãofalse |
dc.title.none.fl_str_mv |
The protein aggregation inhibitor YAT2150 has potent antimalarial activity in Plasmodium falciparum in vitro cultures |
title |
The protein aggregation inhibitor YAT2150 has potent antimalarial activity in Plasmodium falciparum in vitro cultures |
spellingShingle |
The protein aggregation inhibitor YAT2150 has potent antimalarial activity in Plasmodium falciparum in vitro cultures Bouzón-Arnáiz, Inés Amyloid pan-inhibitors Antimalarial drugs Malaria Plasmodium falciparum Protein aggregation YAT2150 |
title_short |
The protein aggregation inhibitor YAT2150 has potent antimalarial activity in Plasmodium falciparum in vitro cultures |
title_full |
The protein aggregation inhibitor YAT2150 has potent antimalarial activity in Plasmodium falciparum in vitro cultures |
title_fullStr |
The protein aggregation inhibitor YAT2150 has potent antimalarial activity in Plasmodium falciparum in vitro cultures |
title_full_unstemmed |
The protein aggregation inhibitor YAT2150 has potent antimalarial activity in Plasmodium falciparum in vitro cultures |
title_sort |
The protein aggregation inhibitor YAT2150 has potent antimalarial activity in Plasmodium falciparum in vitro cultures |
author |
Bouzón-Arnáiz, Inés |
author_facet |
Bouzón-Arnáiz, Inés Avalos-Padilla, Yunuen Biosca, Arnau Caño-Prades, Omar Román-Álamo, Lucía Valle, Javier Andreu, David Moita, Diana Prudêncio, Miguel Arce, Elsa M. Muñoz-Torrero, Diego Fernàndez-Busquets, Xavier |
author_role |
author |
author2 |
Avalos-Padilla, Yunuen Biosca, Arnau Caño-Prades, Omar Román-Álamo, Lucía Valle, Javier Andreu, David Moita, Diana Prudêncio, Miguel Arce, Elsa M. Muñoz-Torrero, Diego Fernàndez-Busquets, Xavier |
author2_role |
author author author author author author author author author author author |
dc.contributor.none.fl_str_mv |
Repositório da Universidade de Lisboa |
dc.contributor.author.fl_str_mv |
Bouzón-Arnáiz, Inés Avalos-Padilla, Yunuen Biosca, Arnau Caño-Prades, Omar Román-Álamo, Lucía Valle, Javier Andreu, David Moita, Diana Prudêncio, Miguel Arce, Elsa M. Muñoz-Torrero, Diego Fernàndez-Busquets, Xavier |
dc.subject.por.fl_str_mv |
Amyloid pan-inhibitors Antimalarial drugs Malaria Plasmodium falciparum Protein aggregation YAT2150 |
topic |
Amyloid pan-inhibitors Antimalarial drugs Malaria Plasmodium falciparum Protein aggregation YAT2150 |
description |
© The Author(s) 2022. 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/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. |
publishDate |
2022 |
dc.date.none.fl_str_mv |
2022-10-26T15:40:40Z 2022 2022-01-01T00:00:00Z |
dc.type.status.fl_str_mv |
info:eu-repo/semantics/publishedVersion |
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info:eu-repo/semantics/article |
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article |
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publishedVersion |
dc.identifier.uri.fl_str_mv |
http://hdl.handle.net/10451/54927 |
url |
http://hdl.handle.net/10451/54927 |
dc.language.iso.fl_str_mv |
eng |
language |
eng |
dc.relation.none.fl_str_mv |
BMC Biol. 2022 Oct 22;20(1):197 10.1186/s12915-022-01374-4 1741-7007 |
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info:eu-repo/semantics/openAccess |
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openAccess |
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application/pdf |
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Springer Nature |
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Springer Nature |
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