Publication: Identificación de nuevas dianas terapéuticas potenciales e inhibidores del sistema ubiquitina proteasoma para el tratamiento de la malaria
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2018-02-15
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Universidad Complutense de Madrid
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Abstract
La malaria es una de las enfermedades infecciosas que producen un mayor número de muertes en el mundo. La mayoría de los casos tienen lugar en África, Ásia y parte de Sudamérica, teniendo un impacto en el desarrollo socioeconómico de los países más pobres. Las formas más severas de malaria son producidas por la infección del parásito protista Plasmodium falciparum (P. falciparum). P. falciparum posee un ciclo de vida complejo, ya que adopta diferentes formas a lo largo de su ciclo vital. La etapa intraeritrocítica es la etapa asociada con la patogénesis, siendo la más estudiada y la principal diana de los fármacos antimaláricos. Sin embargo, la aparición de resistencias frente a todos los antimaláricos conocidos, han llevado a la necesidad de desarrollar nuevos medicamentos con mecanismos de acción novedosos, y a la identificación y validación de nuevas dianas terapéuticas. El Sistema Ubiquitina Proteasoma (UPS) es una de las pocas dianas terapéuticas que pueden ser consideradas como validadas en P. falciparum. Los inhibidores de proteasoma humano inhiben el crecimiento del parásito, incluso en cepas resistentes a antimaláricos y en varias etapas de su ciclo de vida. Un número creciente de compuestos que inhiben alguno de los componentes del UPS humano se encuentran en fases clínicas para el tratamiento de enfermedades como el cáncer. Sin embargo, existe la necesidad de encontrar compuestos que inhiban específicamente alguno de los componentes del UPS de P. falciparum con el fin de evitar cualquier tipo de toxicidad. A pesar de ello, el conocimiento del UPS de P. falciparum es limitado, dificultando el desarrollo de nuevos fármacos...
Malaria is one of the deadliest infectious diseases in the world. Majority of the cases occur in Africa, Asia and parts of South America, impacting economic development in many impoverished countries. The most severe form of malaria is produced by the infection of the protozoan parasite Plasmodium falciparum (P. falciparum). P. falciparum has a complex multistage life cycle. The intraetrythrocytic stage is associated with pathogenesis, being the primary target for antimalarials. Spreading resistance to current treatments urges the need for new drugs with new modes of action and identification and validation of novel drug targets. The ubiquitin proteasome system (UPS) is one of the few chemically validated pathways for P. falciparum. Human proteasome inhibitors can efficiently inhibit P. falciparum-resistant strains at various stages of the cycle. Several compounds targeting the human UPS have entered clinical phases, validating this pathway for cancer treatment. Inhibitors targeting specifically different components of the parasite UPS are desirable to reduce possible side effects. Despite of that, little is known about this system in the parasite, hindering the drug development. The UPS is regulated by several post-translational modification and controls many essential cellular processes such as cell cycle, apoptosis, DNA repair, protein trafficking, etc. Moreover, this system has been frequently associated with hostpathogen interactions since it is implicated in antigen processing and host immune system bypass. P. falciparum modifies the host proteome by completely transforming the erythrocytes into a niche where it can grow but the mechanisms used to achieve that are presently unknown...
Malaria is one of the deadliest infectious diseases in the world. Majority of the cases occur in Africa, Asia and parts of South America, impacting economic development in many impoverished countries. The most severe form of malaria is produced by the infection of the protozoan parasite Plasmodium falciparum (P. falciparum). P. falciparum has a complex multistage life cycle. The intraetrythrocytic stage is associated with pathogenesis, being the primary target for antimalarials. Spreading resistance to current treatments urges the need for new drugs with new modes of action and identification and validation of novel drug targets. The ubiquitin proteasome system (UPS) is one of the few chemically validated pathways for P. falciparum. Human proteasome inhibitors can efficiently inhibit P. falciparum-resistant strains at various stages of the cycle. Several compounds targeting the human UPS have entered clinical phases, validating this pathway for cancer treatment. Inhibitors targeting specifically different components of the parasite UPS are desirable to reduce possible side effects. Despite of that, little is known about this system in the parasite, hindering the drug development. The UPS is regulated by several post-translational modification and controls many essential cellular processes such as cell cycle, apoptosis, DNA repair, protein trafficking, etc. Moreover, this system has been frequently associated with hostpathogen interactions since it is implicated in antigen processing and host immune system bypass. P. falciparum modifies the host proteome by completely transforming the erythrocytes into a niche where it can grow but the mechanisms used to achieve that are presently unknown...
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Tesis inédita de la Universidad Complutense de Madrid, Facultad de Farmacia, Departamento de Bioquímica y Biología Molecular, leída el 22-03-2017