Targeting Plasmodium falciparum protein aggregation as a new antimalarial design strategy
[eng] Malaria caused 241 million cases and 627,000 deaths worldwide in 2020, representing one of the biggest threats for global health nowadays. The currently available arsenal of antimalarial drugs is insufficient to progress towards eradication of the disease, a scenario that is worsened by the ra...
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| Tipo de documento: | tese |
| Estado: | Versão publicada |
| Data de publicação: | 2022 |
| País: | España |
| Recursos: | Universidad de Barcelona |
| Repositório: | Dipòsit Digital de la UB |
| OAI Identifier: | oai:diposit.ub.edu:2445/192704 |
| Acesso em linha: | https://hdl.handle.net/2445/192704 http://hdl.handle.net/10803/687528 |
| Access Level: | Acceso aberto |
| Palavra-chave: | Parasitologia mèdica Malària Plasmodium falciparum Medicaments antipalúdics Medical parasitology Malaria Antimalarials |
| Resumo: | [eng] Malaria caused 241 million cases and 627,000 deaths worldwide in 2020, representing one of the biggest threats for global health nowadays. The currently available arsenal of antimalarial drugs is insufficient to progress towards eradication of the disease, a scenario that is worsened by the rampant evolution of resistance by Plasmodium, the causative agent of malaria. Protein aggregation in malaria parasites is prominent during their whole life cycle. Aggregative proteins are distributed throughout the parasite’s cytosol, especially in the endoplasmic reticulum adjacent areas, where protein translation and folding take place. In this thesis, we intended to target the aggregative features of the Plasmodium falciparum proteome with the final objective of developing an effective antimalarial strategy. Firstly, based on in silico and in vivo data, we selected a group of aggregative peptides present in parasite proteins. Those peptides formed aggregates in vitro; however, attempts to further increase the high aggregation propensity of the P. falciparum proteome by delivering them to in vitro cultures did not significantly decrease the viability of the pathogen. To confirm the lack of activity of the peptides on P. falciparum viability, their entrance inside the parasite was improved combining two different methods: their tagging with cell-penetrating peptides and their encapsulation inside ghost red blood cells. Despite the significantly enhanced entrance of the peptides inside parasites using these two approaches, P. falciparum growth was not affected. To test the alternative hypothesis, i.e. if inhibiting protein aggregation in the parasite might impair its development, we treated in vitro cultures with amyloid pan-inhibitors, which are molecules able to prevent amyloid fibril formation. All of these compounds showed some extent of antiplasmodial activity. Particularly one of them, the double pyridinium salt YAT2150, exhibited potent antimalarial activity with an in vitro IC50 of 90 nM. This drug was also effective on the sexual forms of P. falciparum and on the hepatic stages of P. berghei. In relation with its mode of action, YAT2150 is a powerful inhibitor of the aggregation of the amyloid β peptide fragment 40 in vitro and it reduced in P. falciparum cultures the amyloid content and the quantity of ubiquitinated proteins, as well as the amount in aggregative proteins detected with thioflavin T. Thus, YAT2150 antimalarial mode of action is the inhibition of protein aggregation in the parasite. Moreover, we observed that YAT2150 resistance emergence is not easily developed by P. falciparum cultures and that already acquired resistances to other antimalarial compounds do not affect YAT2150 activity. In this thesis we show that targeting P. falciparum protein aggregation is a valid antimalarial strategy and that YAT2150, belonging to a chemical family with no other antimalarials described, acting through a new antiparasitic mechanism not shared by other currently used drugs, and targeting many gene products, is a good candidate to significantly contribute to malaria eradication. |
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