Leveraging the Aggregated Protein Dye YAT2150 for Malaria Chemotherapy.

IF 4.9 3区 医学 Q1 PHARMACOLOGY & PHARMACY Pharmaceutics Pub Date : 2024-09-30 DOI:10.3390/pharmaceutics16101290
Claudia Camarero-Hoyos, Inés Bouzón-Arnáiz, Yunuen Avalos-Padilla, Antonino Nicolò Fallica, Lucía Román-Álamo, Miriam Ramírez, Emma Portabella, Ona Cuspinera, Daniela Currea-Ayala, Marc Orozco-Quer, Maria Ribera, Inga Siden-Kiamos, Lefteris Spanos, Valentín Iglesias, Benigno Crespo, Sara Viera, David Andreu, Elena Sulleiro, Francesc Zarzuela, Nerea Urtasun, Sandra Pérez-Torras, Marçal Pastor-Anglada, Elsa M Arce, Diego Muñoz-Torrero, Xavier Fernàndez-Busquets
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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.

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利用聚合蛋白质染料 YAT2150 进行疟疾化疗。
背景/目的:YAT2150 是一种首创的抗疟化合物,最近被提议作为一种治疗疟疾的有趣新药。方法/结果:YAT2150 进入疟原虫体内后荧光迅速增强,这一特性可用于设计高灵敏度的诊断方法。YAT2150 可阻断疟原虫卵子阶段的体外发育,加入受感染的血餐中后,可抑制蚊子体内卵囊的形成。因此,该化合物可能有助于未来的传播阻断抗疟战略。在 Caco-2 细胞中进行的细胞流入/流出研究表明,YAT2150 可通过内吞和 OATP2B1 转运体内化,而其主要的输出途径是 OSTα。YAT2150 具有良好的药物代谢和药代动力学特征,其中等程度的细胞毒性在被免疫脂质体包裹后可显著降低,从而使药物选择性指数急剧上升到接近 1000 的值。虽然 YAT2150 能与淀粉样肽结合,但其体外荧光发射在与形成无定形聚集体的肽结合时更强,这表明富含非结构化蛋白质的区域是药物在疟原虫细胞内的优先结合位点。在使用氯喹和伯氨喹等喹啉类抗疟药物治疗后,也能观察到寄生虫在接受 YAT2150 治疗后蛋白质聚集的减少,这被认为与该药物的作用模式直接相关。结论总之,本文提供的数据表明,YAT2150 可作为用于疟疾诊断和治疗的新型化合物家族的先锋,因为它的作用模式据推测是基于与病原体中的功能性蛋白聚集体相互作用。
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来源期刊
Pharmaceutics
Pharmaceutics Pharmacology, Toxicology and Pharmaceutics-Pharmaceutical Science
CiteScore
7.90
自引率
11.10%
发文量
2379
审稿时长
16.41 days
期刊介绍: Pharmaceutics (ISSN 1999-4923) is an open access journal which provides an advanced forum for the science and technology of pharmaceutics and biopharmaceutics. It publishes reviews, regular research papers, communications,  and short notes. Covered topics include pharmacokinetics, toxicokinetics, pharmacodynamics, pharmacogenetics and pharmacogenomics, and pharmaceutical formulation. Our aim is to encourage scientists to publish their experimental and theoretical details in as much detail as possible. There is no restriction on the length of the papers. The full experimental details must be provided so that the results can be reproduced.
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