Leveraging the aggregated protein dye YAT2150 for malaria chemotherapy

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• dc.contributor.author Camarero-Hoyos, Claudia
• dc.contributor.author Bouzón-Arnáiz, Inés
• dc.contributor.author Avalos-Padilla, Yunuen
• dc.contributor.author Fallica, Antonino Nicolò
• dc.contributor.author Román-Álamo, Lucía
• dc.contributor.author Ramírez, Miriam
• dc.contributor.author Portabella, Emma
• dc.contributor.author Cuspinera, Ona
• dc.contributor.author Currea-Ayala, Daniela
• dc.contributor.author Orozco-Quer, Marc
• dc.contributor.author Ribera, Maria
• dc.contributor.author Iglesias, Valentin
• dc.contributor.author Andreu Martínez, David
• dc.contributor.author Fernàndez Busquets, Xavier
• dc.date.accessioned 2025-01-15T07:23:10Z
• dc.date.available 2025-01-15T07:23:10Z
• dc.date.issued 2024
• dc.description.abstract 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.
• dc.description.sponsorship 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.
• dc.format.mimetype application/pdf
• dc.identifier.citation Camarero-Hoyos C, Bouzón-Arnáiz I, Avalos-Padilla Y, Fallica AN, Román-Álamo L, Ramírez M, et al. Leveraging the aggregated protein dye YAT2150 for malaria chemotherapy. Pharmaceutics. 2024 Sep 30;16(10):1290. DOI: 10.3390/pharmaceutics16101290
• dc.identifier.doi http://dx.doi.org/10.3390/pharmaceutics16101290
• dc.identifier.issn 1999-4923
• dc.identifier.uri http://hdl.handle.net/10230/69127
• dc.language.iso eng
• dc.publisher MDPI
• dc.relation.ispartof Pharmaceutics. 2024 Sep 30;16(10):1290
• dc.relation.projectID info:eu-repo/grantAgreement/ES/3PE/PID2021-128325OB-I00
• dc.relation.projectID info:eu-repo/grantAgreement/ES/3PE/PDC2022-133085-I00
• dc.rights © 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/).
• dc.rights.accessRights info:eu-repo/semantics/openAccess
• dc.rights.uri https://creativecommons.org/licenses/by/4.0/
• dc.subject.keyword Plasmodium falciparum
• dc.subject.keyword YAT2150
• dc.subject.keyword Malaria
• dc.subject.keyword Protein aggregation
• dc.subject.keyword info:eu-repo/grantAgreement/ES/2PE/PID2020-118127RB-I00
• dc.subject.keyword info:eu-repo/grantAgreement/ES/2PE/AGL2017-84097-C2-2-R
• dc.subject.keyword info:eu-repo/grantAgreement/ES/3PE/PID2021-124765OB-I00
• dc.title Leveraging the aggregated protein dye YAT2150 for malaria chemotherapy
• dc.type info:eu-repo/semantics/article
• dc.type.version info:eu-repo/semantics/publishedVersion