Leveraging the aggregated protein dye YAT2150 for malaria chemotherapy

Background/Objectives: YAT2150 is a first-in-class antiplasmodial compound that has been recently proposed as a new interesting drug for malaria therapy. Methods/Results: The fluorescence of YAT2150 rapidly increases upon its entry into Plasmodium, a property that can be of use for the design of hig...

Full description

Bibliographic Details
Authors: Camarero-Hoyos, Claudia, Bouzón-Arnáiz, Inés, Avalos-Padilla, Yunuen, Fallica, Antonino Nicolò, Román-Álamo, Lucía, Ramírez, Miriam, Portabella, Emma, Cuspinera, Ona, Currea-Ayala, Daniela, Orozco-Quer, Marc, Ribera, Maria, Iglesias, Valentin, Andreu Martínez, David, Fernàndez Busquets, Xavier
Format: article
Status:Published version
Publication Date:2024
Country:España
Institution:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
Repository:Recercat. Dipósit de la Recerca de Catalunya
OAI Identifier:oai:recercat.cat:10230/69127
Online Access:http://hdl.handle.net/10230/69127
http://dx.doi.org/10.3390/pharmaceutics16101290
Access Level:Open access
Keyword:Plasmodium falciparum
YAT2150
Malaria
Protein aggregation
info:eu-repo/grantAgreement/ES/2PE/PID2020-118127RB-I00
info:eu-repo/grantAgreement/ES/2PE/AGL2017-84097-C2-2-R
info:eu-repo/grantAgreement/ES/3PE/PID2021-124765OB-I00
id ES_ebfadf98f5b27746fc3573ddccaed5d5
oai_identifier_str oai:recercat.cat:10230/69127
network_acronym_str ES
network_name_str España
repository_id_str
dc.title.none.fl_str_mv Leveraging the aggregated protein dye YAT2150 for malaria chemotherapy
title Leveraging the aggregated protein dye YAT2150 for malaria chemotherapy
spellingShingle Leveraging the aggregated protein dye YAT2150 for malaria chemotherapy
Camarero-Hoyos, Claudia
Plasmodium falciparum
YAT2150
Malaria
Protein aggregation
info:eu-repo/grantAgreement/ES/2PE/PID2020-118127RB-I00
info:eu-repo/grantAgreement/ES/2PE/AGL2017-84097-C2-2-R
info:eu-repo/grantAgreement/ES/3PE/PID2021-124765OB-I00
title_short Leveraging the aggregated protein dye YAT2150 for malaria chemotherapy
title_full Leveraging the aggregated protein dye YAT2150 for malaria chemotherapy
title_fullStr Leveraging the aggregated protein dye YAT2150 for malaria chemotherapy
title_full_unstemmed Leveraging the aggregated protein dye YAT2150 for malaria chemotherapy
title_sort Leveraging the aggregated protein dye YAT2150 for malaria chemotherapy
dc.creator.none.fl_str_mv Camarero-Hoyos, Claudia
Bouzón-Arnáiz, Inés
Avalos-Padilla, Yunuen
Fallica, Antonino Nicolò
Román-Álamo, Lucía
Ramírez, Miriam
Portabella, Emma
Cuspinera, Ona
Currea-Ayala, Daniela
Orozco-Quer, Marc
Ribera, Maria
Iglesias, Valentin
Andreu Martínez, David
Fernàndez Busquets, Xavier
author Camarero-Hoyos, Claudia
author_facet Camarero-Hoyos, Claudia
Bouzón-Arnáiz, Inés
Avalos-Padilla, Yunuen
Fallica, Antonino Nicolò
Román-Álamo, Lucía
Ramírez, Miriam
Portabella, Emma
Cuspinera, Ona
Currea-Ayala, Daniela
Orozco-Quer, Marc
Ribera, Maria
Iglesias, Valentin
Andreu Martínez, David
Fernàndez Busquets, Xavier
author_role author
author2 Bouzón-Arnáiz, Inés
Avalos-Padilla, Yunuen
Fallica, Antonino Nicolò
Román-Álamo, Lucía
Ramírez, Miriam
Portabella, Emma
Cuspinera, Ona
Currea-Ayala, Daniela
Orozco-Quer, Marc
Ribera, Maria
Iglesias, Valentin
Andreu Martínez, David
Fernàndez Busquets, Xavier
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Plasmodium falciparum
YAT2150
Malaria
Protein aggregation
info:eu-repo/grantAgreement/ES/2PE/PID2020-118127RB-I00
info:eu-repo/grantAgreement/ES/2PE/AGL2017-84097-C2-2-R
info:eu-repo/grantAgreement/ES/3PE/PID2021-124765OB-I00
topic Plasmodium falciparum
YAT2150
Malaria
Protein aggregation
info:eu-repo/grantAgreement/ES/2PE/PID2020-118127RB-I00
info:eu-repo/grantAgreement/ES/2PE/AGL2017-84097-C2-2-R
info:eu-repo/grantAgreement/ES/3PE/PID2021-124765OB-I00
description Background/Objectives: YAT2150 is a first-in-class antiplasmodial compound that has been recently proposed as a new interesting drug for malaria therapy. Methods/Results: The fluorescence of YAT2150 rapidly increases upon its entry into Plasmodium, a property that can be of use for the design of highly sensitive diagnostic approaches. YAT2150 blocks the in vitro development of the ookinete stage of Plasmodium and, when added to an infected blood meal, inhibits oocyst formation in the mosquito. Thus, the compound could possibly contribute to future transmission-blocking antimalarial strategies. Cell influx/efflux studies in Caco-2 cells suggest that YAT2150 is internalized by endocytosis and also through the OATP2B1 transporter, whereas its main export route would be via OSTα. YAT2150 has an overall favorable drug metabolism and pharmacokinetics profile, and its moderate cytotoxicity can be significantly reduced upon encapsulation in immunoliposomes, which leads to a dramatic increase in the drug selectivity index to values close to 1000. Although YAT2150 binds amyloid-forming peptides, its in vitro fluorescence emission is stronger upon association with peptides that form amorphous aggregates, suggesting that regions enriched in unstructured proteins are the preferential binding sites of the drug inside Plasmodium cells. The reduction of protein aggregation in the parasite after YAT2150 treatment, which has been suggested to be directly related to the drug's mode of action, is also observed following treatment with quinoline antimalarials like chloroquine and primaquine. Conclusions: Altogether, the data presented here indicate that YAT2150 can represent the spearhead of a new family of compounds for malaria diagnosis and therapy due to its presumed novel mode of action based on the interaction with functional protein aggregates in the pathogen.
publishDate 2024
dc.date.none.fl_str_mv 2024
2025
2025
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 http://hdl.handle.net/10230/69127
http://dx.doi.org/10.3390/pharmaceutics16101290
url http://hdl.handle.net/10230/69127
http://dx.doi.org/10.3390/pharmaceutics16101290
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv Pharmaceutics. 2024 Sep 30;16(10):1290
info:eu-repo/grantAgreement/ES/3PE/PID2021-128325OB-I00
info:eu-repo/grantAgreement/ES/3PE/PDC2022-133085-I00
dc.rights.none.fl_str_mv https://creativecommons.org/licenses/by/4.0/
info:eu-repo/semantics/openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by/4.0/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
application/pdf
dc.publisher.none.fl_str_mv MDPI
publisher.none.fl_str_mv MDPI
dc.source.none.fl_str_mv reponame:Recercat. Dipósit de la Recerca de Catalunya
instname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
instname_str Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
reponame_str Recercat. Dipósit de la Recerca de Catalunya
collection Recercat. Dipósit de la Recerca de Catalunya
repository.name.fl_str_mv
repository.mail.fl_str_mv
_version_ 1869423275156701184
spelling Leveraging the aggregated protein dye YAT2150 for malaria chemotherapyCamarero-Hoyos, ClaudiaBouzón-Arnáiz, InésAvalos-Padilla, YunuenFallica, Antonino NicolòRomán-Álamo, LucíaRamírez, MiriamPortabella, EmmaCuspinera, OnaCurrea-Ayala, DanielaOrozco-Quer, MarcRibera, MariaIglesias, ValentinAndreu Martínez, DavidFernàndez Busquets, XavierPlasmodium falciparumYAT2150MalariaProtein aggregationinfo:eu-repo/grantAgreement/ES/2PE/PID2020-118127RB-I00info:eu-repo/grantAgreement/ES/2PE/AGL2017-84097-C2-2-Rinfo:eu-repo/grantAgreement/ES/3PE/PID2021-124765OB-I00Background/Objectives: YAT2150 is a first-in-class antiplasmodial compound that has been recently proposed as a new interesting drug for malaria therapy. Methods/Results: The fluorescence of YAT2150 rapidly increases upon its entry into Plasmodium, a property that can be of use for the design of highly sensitive diagnostic approaches. YAT2150 blocks the in vitro development of the ookinete stage of Plasmodium and, when added to an infected blood meal, inhibits oocyst formation in the mosquito. Thus, the compound could possibly contribute to future transmission-blocking antimalarial strategies. Cell influx/efflux studies in Caco-2 cells suggest that YAT2150 is internalized by endocytosis and also through the OATP2B1 transporter, whereas its main export route would be via OSTα. YAT2150 has an overall favorable drug metabolism and pharmacokinetics profile, and its moderate cytotoxicity can be significantly reduced upon encapsulation in immunoliposomes, which leads to a dramatic increase in the drug selectivity index to values close to 1000. Although YAT2150 binds amyloid-forming peptides, its in vitro fluorescence emission is stronger upon association with peptides that form amorphous aggregates, suggesting that regions enriched in unstructured proteins are the preferential binding sites of the drug inside Plasmodium cells. The reduction of protein aggregation in the parasite after YAT2150 treatment, which has been suggested to be directly related to the drug's mode of action, is also observed following treatment with quinoline antimalarials like chloroquine and primaquine. Conclusions: Altogether, the data presented here indicate that YAT2150 can represent the spearhead of a new family of compounds for malaria diagnosis and therapy due to its presumed novel mode of action based on the interaction with functional protein aggregates in the pathogen.This work was supported by grants (i) PID2021-128325OB-I00, PDC2022-133085-I00 (X.F.-B.) and PID2020-118127RB-I00 (D.M.-T.), funded by Ministerio de Ciencia, Innovación y Universidades/Agencia Estatal de Investigación (MICIU/AEI/10.13039/501100011033), which included ERDF funds; (ii) II Premis Innovació Campus Clínic 2022, Hospital Clínic de Barcelona (X.F.-B.); and (iii) Generalitat de Catalunya, Spain (http://agaur.gencat.cat/, accessed on 10 June 2021), grant numbers 2021-SGR-00635 (X.F.-B.) and 2021-SGR-00357 (D.M.-T.). Work at Pompeu Fabra University was supported by “La Caixa” Banking Foundation (https://fundacionlacaixa.org/, accessed on 10 June 2021, 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. Work at the MPET laboratory (IBUB, CIBEREHD, IRSJD) was supported by grant PID2021-124765OB-I00 funded by MICIU/AEI/10.13039/501100011033 and by “FEDER: a way of making Europe” (M.P.-A. and S.P.-T.). CIBER is an initiative of Instituto de Salud Carlos III. The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of this manuscript.MDPI202520252024info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionapplication/pdfapplication/pdfhttp://hdl.handle.net/10230/69127http://dx.doi.org/10.3390/pharmaceutics16101290reponame:Recercat. Dipósit de la Recerca de Catalunyainstname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)InglésPharmaceutics. 2024 Sep 30;16(10):1290info:eu-repo/grantAgreement/ES/3PE/PID2021-128325OB-I00info:eu-repo/grantAgreement/ES/3PE/PDC2022-133085-I00© 2024 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).https://creativecommons.org/licenses/by/4.0/info:eu-repo/semantics/openAccessoai:recercat.cat:10230/691272026-05-29T05:05:01Z
score 15,812429

Similar Items