Leveraging the Aggregated Protein Dye YAT2150 for Malaria Chemotherapy

<b>Background/Objectives</b>: YAT2150 is a first-in-class antiplasmodial compound that has been recently proposed as a new interesting drug for malaria therapy. <b>Methods/Results</b>: The fluorescence of YAT2150 rapidly increases upon its entry into <i>Plasmodium</i>, 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 <i>Plasmodium</i> 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 <i>Plasmodium</i> 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. <b>Conclusions</b>: 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.

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Publication Details

Journal
Pharmaceutics
Published
2024-09-30
DOI
https://doi.org/10.3390/pharmaceutics16101290
Citations
1
Primary Topic
vaccines and immunoinformatics approaches
Type
article
Field-Weighted Citation Impact
0.23

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article

Leveraging the Aggregated Protein Dye YAT2150 for Malaria Chemotherapy

Valentín Iglesias, Benigno Crespo, Antonino N. Fallica, Diego Muñoz‐Torrero et al.
1 citations
Pharmaceutics
vaccines and immunoinformatics approaches
0.23
article

Leveraging the Aggregated Protein Dye YAT2150 for Malaria Chemotherapy

Valentín Iglesias, Benigno Crespo, Antonino N. Fallica, Diego Muñoz‐Torrero, Inga Sidén‐Kiamos, Elena Sulleiro, Marçal Pastor‐Anglada, Lefteris Spanos, Elsa M. Arce, Miriam Ramírez, Sara Viera, Nerea Urtasun, Sandra Pérez‐Torras, Francesc Zarzuela, Xavier Fernàndez‐Busquets, Lucía Román-Álamo, Inés Bouzón‐Arnáiz, Yunuen Avalos‐Padilla, David Andreu, Claudia Camarero-Hoyos, Marc Orozco-Quer, Emma Portabella, Ona Cuspinera, Daniela Currea-Ayala, M. Ribera
article en
1 citations

Abstract

<b>Background/Objectives</b>: YAT2150 is a first-in-class antiplasmodial compound that has been recently proposed as a new interesting drug for malaria therapy. <b>Methods/Results</b>: The fluorescence of YAT2150 rapidly increases upon its entry into <i>Plasmodium</i>, 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 <i>Plasmodium</i> 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 <i>Plasmodium</i> 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. <b>Conclusions</b>: 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.

PharmaceuticsVol. 16(10)
Universitat Autònoma de Barcelona (ES), Hospital Sant Joan de Déu Barcelona (ES), Medical University of Białystok (PL), Universitat Pompeu Fabra (ES), Instituto de Salud Carlos III (ES), Barcelona Biomedical Research Park (ES), FORTH Institute of Molecular Biology and Biotechnology (GR), Centro de Investigación Biomédica en Red (ES), Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (ES), Institute for Bioengineering of Catalonia (ES), Barcelona Institute for Global Health (ES), GlaxoSmithKline (Spain) (ES), Universitat de Barcelona (ES)
GlaxoSmithKline, Fundación Ramón Areces, “la Caixa” Foundation, Comunidad de Madrid, Centres de Recerca de Catalunya, European Commission, Generalitat de Catalunya, Ministerio de Ciencia e Innovación, Universitat Autònoma de Barcelona, Narodowa Agencja Wymiany Akademickiej, National Institutes of Health, National Institute of Allergy and Infectious Diseases, Direcció General de Recerca, Generalitat de Catalunya
Good health and well-being
Openalex Percentile: Top 42%
vaccines and immunoinformatics approaches
0.23
DOIOpen Access PDFOpenAlex
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