Aptamer-based inhibition of vesicle trafficking as a new therapeutic strategy against malaria

Group: Nanomalaria and Targeted therapeutics and nanodevices
Group leader: Xavier Fernandez-Busquets (xfernandez@ibecbarcelona.eu) and Silvia Muro (smuro@ibecbarcelona.eu)

Research project:

Malaria is a life threatening disease caused by the protist parasite Plasmodium. Despite of the available drug treatments, malaria still represents a world health problem due to the occurrence of drug resistance. Therefore, new and alternative therapeutic approaches are required to eradicate this disease. One of the key mechanisms involved in the establishment of Plasmodium infection is the transport of virulence proteins from the parasite’s organelles to the cytoplasm of the host red blood cell or to the extracellular space. Recently, our group has discovered that Plasmodium falciparum, the deadliest human malaria parasite species, possesses a minimal endosomal sorting complex required for transport (ESCRT) machinery involved in the production of extracellular vesicles, which mediate protein export during the intraerythrocytic life cycle of the parasite.

Taking advantage of the low amino acid sequence conservation between Plasmodium and human ESCRT proteins, the main goal of this PhD thesis will be to develop different strategies to specifically target and block the action of ESCRT proteins from the parasite. For this purpose, the student will use different approaches including polyclonal antibodies, DNA aptamer-based inhibitors of ESCRT proteins and proteolysis-targeting chimeric molecules (PROTACs). For improved delivery, these molecules will be encapsulated in targeted nanocarriers whose kinetics, mechanism, and destination can be modulated by varying size, shape and targeting valency, combining binding to several receptors, or coupling targeting and anti-phagocytic moieties on the surface of drug carriers. The project will combine the analysis of the mentioned therapeutic approaches in cultured cells, in in vivo systems such as BALB/c mice as a model and in synthetic membrane models to test different delivery systems. This project will be done in the Nanomalaria and Targeted Therapeutic groups at IBEC, and will be co-supervised by Yunuen Ávalos-Padilla.

 

Job position description:

We will look for an enthusiastic, organized and autonomous candidate with a degree in Biotechnology, Biochemistry, Biology or similar areas who is interested in developing her/his postdoctoral project in the context of the project. During year 1, the fellow will be trained by the team on all the techniques that will be used during the study, especially in the in vitro culture of malaria parasites and in PROTAC technology. The fellow will start the screening of currently existing antibodies raised against P. falciparum ESCRT proteins for their potential growth inhibition of the parasite to establish the best target-candidates. During year 2, the fellow will develop DNA aptamers against the recombinant P. falciparum ESCRT proteins available in the group and will explore their capacity to block vesicle generation in femtoinjection assays and their antimalarial activities in live P. falciparum cultures. During year 3, in vivo assays in mice will be performed, together with completion of all analyses, statistics, interpretation of results, and writing of the PhD Thesis. During the last semester, scientific articles will be written and the results will be presented at national (Spanish Society of Infectious Diseases and Microbiology) and international congresses (Pan-African Malaria Conference). One three-month stay will be done at the Max Planck Institute for Colloids and Interfaces in Golm (Germany) during year 2 for the presentation of the intermediate results of the study and training on different approaches for targeted delivery of aptamers/PROTACs in different membrane models and their biophysical characterization. During the 3 years of the fellowship, the PhD fellow will acquire a strong knowledge of parasitology and molecular biology of malaria; s/he will acquire this knowledge through her/his work, regular meetings with the PhD co-supervisors, bi-weekly journal clubs and weekly group meetings, as well as through daily readings of literature related to the field.