Targeting Plasmodium falciparum protein aggregation as a new antimalarial design strategy

Programa de Doctorat en Biotecnologia / Tesi realitzada a l'Institut de Bioengenyeria de Catalunya (IBEC) - Institut de Salut Global de Barcelona (ISGlobal)

Detalhes bibliográficos
Autor: Bouzón Arnáiz, Inés
Formato: tesis doctoral
Estado:Versión publicada
Fecha de publicación:2022
País:España
Recursos:CBUC, CESCA
Repositorio:TDR. Tesis Doctorales en Red
OAI Identifier:oai:www.tdx.cat:10803/687528
Acesso em linha:http://hdl.handle.net/10803/687528
Access Level:acceso abierto
Palavra-chave:Parasitologia mèdica
Parasitología médica
Medical parasitology
Malària
Paludismo
Malaria
Plasmodium falciparum
Medicaments antipalúdics
Medicamentos antipalúdicos
Antimalarials
Ciències de la Salut
615
id ES_cca7ab60b60d7ea8160c16d6479be8e6
oai_identifier_str oai:www.tdx.cat:10803/687528
network_acronym_str ES
network_name_str España
repository_id_str
dc.title.none.fl_str_mv Targeting Plasmodium falciparum protein aggregation as a new antimalarial design strategy
title Targeting Plasmodium falciparum protein aggregation as a new antimalarial design strategy
spellingShingle Targeting Plasmodium falciparum protein aggregation as a new antimalarial design strategy
Bouzón Arnáiz, Inés
Parasitologia mèdica
Parasitología médica
Medical parasitology
Malària
Paludismo
Malaria
Plasmodium falciparum
Medicaments antipalúdics
Medicamentos antipalúdicos
Antimalarials
Ciències de la Salut
615
title_short Targeting Plasmodium falciparum protein aggregation as a new antimalarial design strategy
title_full Targeting Plasmodium falciparum protein aggregation as a new antimalarial design strategy
title_fullStr Targeting Plasmodium falciparum protein aggregation as a new antimalarial design strategy
title_full_unstemmed Targeting Plasmodium falciparum protein aggregation as a new antimalarial design strategy
title_sort Targeting Plasmodium falciparum protein aggregation as a new antimalarial design strategy
dc.creator.none.fl_str_mv Bouzón Arnáiz, Inés
author Bouzón Arnáiz, Inés
author_facet Bouzón Arnáiz, Inés
author_role author
dc.contributor.none.fl_str_mv Fernàndez Busquets, Xavier
Badía Palacín, Josefa
Universitat de Barcelona. Facultat de Farmàcia i Ciències de l'Alimentació
dc.subject.none.fl_str_mv Parasitologia mèdica
Parasitología médica
Medical parasitology
Malària
Paludismo
Malaria
Plasmodium falciparum
Medicaments antipalúdics
Medicamentos antipalúdicos
Antimalarials
Ciències de la Salut
615
topic Parasitologia mèdica
Parasitología médica
Medical parasitology
Malària
Paludismo
Malaria
Plasmodium falciparum
Medicaments antipalúdics
Medicamentos antipalúdicos
Antimalarials
Ciències de la Salut
615
description Programa de Doctorat en Biotecnologia / Tesi realitzada a l'Institut de Bioengenyeria de Catalunya (IBEC) - Institut de Salut Global de Barcelona (ISGlobal)
publishDate 2022
dc.date.none.fl_str_mv 2022
2023
2023
dc.type.none.fl_str_mv info:eu-repo/semantics/doctoralThesis
info:eu-repo/semantics/publishedVersion
format doctoralThesis
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/10803/687528
url http://hdl.handle.net/10803/687528
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.rights.none.fl_str_mv http://creativecommons.org/licenses/by-nc-nd/4.0/
info:eu-repo/semantics/openAccess
rights_invalid_str_mv http://creativecommons.org/licenses/by-nc-nd/4.0/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv 270 p.
application/pdf
dc.publisher.none.fl_str_mv Universitat de Barcelona
publisher.none.fl_str_mv Universitat de Barcelona
dc.source.none.fl_str_mv TDX (Tesis Doctorals en Xarxa)
reponame:TDR. Tesis Doctorales en Red
instname:CBUC, CESCA
instname_str CBUC, CESCA
reponame_str TDR. Tesis Doctorales en Red
collection TDR. Tesis Doctorales en Red
repository.name.fl_str_mv
repository.mail.fl_str_mv
_version_ 1869419739588067328
spelling Targeting Plasmodium falciparum protein aggregation as a new antimalarial design strategyBouzón Arnáiz, InésParasitologia mèdicaParasitología médicaMedical parasitologyMalàriaPaludismoMalariaPlasmodium falciparumMedicaments antipalúdicsMedicamentos antipalúdicosAntimalarialsCiències de la Salut615Programa de Doctorat en Biotecnologia / Tesi realitzada a l'Institut de Bioengenyeria de Catalunya (IBEC) - Institut de Salut Global de Barcelona (ISGlobal)[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.[eng] Se estima que en el año 2020 se produjeron en todo el mundo 241 millones de casos de malaria. Esta enfermedad, causada por parásitos del género Plasmodium, sigue siendo una gran amenaza para la salud global. Sin embargo, los antipalúdicos usados actualmente son insuficientes para combatir la malaria, especialmente porque se han detectado parásitos resistentes a la gran mayoría de ellos. Por otro lado, sabemos que la agregación de proteínas en Plasmodium es prominente, de hecho aquí mostramos que se detecta en todas las fases del desarrollo del parásito. Esta tesis se centra, precisamente, en el uso de las proteínas agregativas de P. falciparum como dianas terapéuticas para el desarrollo de nuevas estrategias antipalúdicas. Exploramos dos hipótesis complementarias: el aumento de los niveles basales de agregación proteica en el parásito mediante la administración de péptidos agregativos presentes en el proteoma de P. falciparum, y la inhibición de la agregación de las proteínas agregativas del parásito mediante el tratamiento con compuestos inhibidores de la formación de amiloides. Mientras la primera estrategia no reduce de manera efectiva la viabilidad del parásito, la segunda sí lo hace. Especialmente, uno de los compuestos testados, YAT2150, tiene un efecto nocivo tanto para las formas asexuales como sexuales de P. falciparum y para las hepáticas de P. berghei. Además, este compuesto inhibe la agregación proteica en P. falciparum in vivo (reduce el contenido de proteínas amiloides, de proteínas ubiquitinadas y de proteínas detectadas por tioflavina-T) y no permite el desarrollo de resistencias en cultivos in vitro del parásito.Universitat de BarcelonaFernàndez Busquets, XavierBadía Palacín, JosefaUniversitat de Barcelona. Facultat de Farmàcia i Ciències de l'Alimentació202320232022info:eu-repo/semantics/doctoralThesisinfo:eu-repo/semantics/publishedVersion270 p.application/pdfhttp://hdl.handle.net/10803/687528TDX (Tesis Doctorals en Xarxa)reponame:TDR. Tesis Doctorales en Redinstname:CBUC, CESCAInglésL'accés als continguts d'aquesta tesi queda condicionat a l'acceptació de les condicions d'ús establertes per la següent llicència Creative Commons: http://creativecommons.org/licenses/by-nc-nd/4.0/http://creativecommons.org/licenses/by-nc-nd/4.0/info:eu-repo/semantics/openAccessoai:www.tdx.cat:10803/6875282026-06-14T12:46:07Z
score 15,300719

Registos relacionados