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| Página principal > Artículos > Artículos publicados > Leveraging the Aggregated Protein Dye YAT2150 for Malaria Chemotherapy |
(Universitat de Barcelona) (Universitat de Barcelona) (Universitat de Barcelona) (Universitat de Barcelona) (Universitat de Barcelona) (Institute of Molecular Biology and Biotechnology (Heraklion, Grècia)) (Universitat Autònoma de Barcelona. Departament de Bioquímica i de Biologia Molecular) (Global Health Medicines R&D, GlaxoSmithKline (Tres Cantos, Espanya)) (Universitat Pompeu Fabra) (Hospital Universitari Vall d'Hebron) (Universitat de Barcelona) (Universitat de Barcelona) (Universitat de Barcelona. Institut de Biomedicina) (Universitat de Barcelona) (Universitat de Barcelona) (Universitat de Barcelona)
| Fecha: | 2024 |
| Resumen: | 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. |
| Ayudas: | Agencia Estatal de Investigación PID2021-128325OB-I00 Agencia Estatal de Investigación PDC2022-133085-I00 Agencia Estatal de Investigación PID2020-118127RB-I00 Agencia Estatal de Investigación AGL2017-84097-C2-2-R Agencia Estatal de Investigación PID2021-124765OB-I00 Generalitat de Catalunya 2021SGR00635 Generalitat de Catalunya 2021SGR00357 "la Caixa" Foundation HR1700409 |
| Derechos: | Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.  |
| Lengua: | Anglès |
| Documento: | Article ; recerca ; Versió publicada |
| Materia: | Plasmodium falciparum ; Malaria ; Protein aggregation ; YAT2150 |
| Publicado en: | Pharmaceutics, Vol. 16 (september 2024) , ISSN 1999-4923 |
