The protein aggregation inhibitor YAT2150 has potent antimalarial activity in Plasmodium falciparum in vitro cultures

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 f...

Descripción completa

Detalles Bibliográficos
Autores: 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 López-Ibarra, Diego, Fernàndez Busquets, Xavier
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2022
País:España
Institución:Universidad de Barcelona
Repositorio:Dipòsit Digital de la UB
OAI Identifier:oai:diposit.ub.edu:2445/190671
Acceso en línea:https://hdl.handle.net/2445/190671
Access Level:acceso abierto
Palabra clave:Plasmodium falciparum
Malària
Microbiologia
Malaria
Microbiology
id ES_98f1fa086b89304dc0dd0fdaccc7beaa
oai_identifier_str oai:diposit.ub.edu:2445/190671
network_acronym_str ES
network_name_str España
repository_id_str
spelling The protein aggregation inhibitor YAT2150 has potent antimalarial activity in Plasmodium falciparum in vitro culturesBouzón Arnáiz, InésAvalos Padilla, YunuenBiosca, ArnauCaño-Prades, OmarRomán-Álamo, LucíaValle, JavierAndreu, DavidMoita, DianaPrudêncio, MiguelArce, Elsa M.Muñoz-Torrero López-Ibarra, DiegoFernàndez Busquets, XavierPlasmodium falciparumMalàriaMicrobiologiaPlasmodium falciparumMalariaMicrobiologyBackground: 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.BioMed Central2022info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionapplication/pdfhttps://hdl.handle.net/2445/190671Articles publicats en revistes (Farmacologia, Toxicologia i Química Terapèutica)reponame:Dipòsit Digital de la UBinstname:Universidad de BarcelonaInglésReproducció del document publicat a: https://doi.org/10.1186/s12915-022-01374-4Bmc Biology, 2022, vol. 20, p. 197https://doi.org/10.1186/s12915-022-01374-4cc-by (c) Bouzón Arnáiz, Inés et al., 2022https://creativecommons.org/licenses/by/4.0/info:eu-repo/semantics/openAccessoai:diposit.ub.edu:2445/1906712026-05-27T06:46:51Z
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
Plasmodium falciparum
Malària
Microbiologia
Plasmodium falciparum
Malaria
Microbiology
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
dc.creator.none.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 López-Ibarra, Diego
Fernàndez Busquets, Xavier
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 López-Ibarra, 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 López-Ibarra, Diego
Fernàndez Busquets, Xavier
author2_role author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Plasmodium falciparum
Malària
Microbiologia
Plasmodium falciparum
Malaria
Microbiology
topic Plasmodium falciparum
Malària
Microbiologia
Plasmodium falciparum
Malaria
Microbiology
description 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.
publishDate 2022
dc.date.none.fl_str_mv 2022
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv https://hdl.handle.net/2445/190671
url https://hdl.handle.net/2445/190671
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv Reproducció del document publicat a: https://doi.org/10.1186/s12915-022-01374-4
Bmc Biology, 2022, vol. 20, p. 197
https://doi.org/10.1186/s12915-022-01374-4
dc.rights.none.fl_str_mv cc-by (c) Bouzón Arnáiz, Inés et al., 2022
https://creativecommons.org/licenses/by/4.0/
info:eu-repo/semantics/openAccess
rights_invalid_str_mv cc-by (c) Bouzón Arnáiz, Inés et al., 2022
https://creativecommons.org/licenses/by/4.0/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv BioMed Central
publisher.none.fl_str_mv BioMed Central
dc.source.none.fl_str_mv Articles publicats en revistes (Farmacologia, Toxicologia i Química Terapèutica)
reponame:Dipòsit Digital de la UB
instname:Universidad de Barcelona
instname_str Universidad de Barcelona
reponame_str Dipòsit Digital de la UB
collection Dipòsit Digital de la UB
repository.name.fl_str_mv
repository.mail.fl_str_mv
_version_ 1869414233847889920
score 15,301603

Similares en LA Referencia