Area of Knowledge: LIFE SCIENCES
We have discovered that protein aggregation has a functional role in the malaria parasite, and have developed a highly promising antimalarial drug (YAT2150) having as presumed mode of action (MoA) the inhibition of protein aggregation in Plasmodium. YAT2150 has a number of characteristics that place it as a highly promising model for a new generation of antimalarial drugs for the post-artemisinin era, among which several molecular targets in the pathogen and a suspected MoA which is not shared by other antimalarials. These two properties make it unlikely a rapid evolution of resistance, as already confirmed in assays that have postulated YAT2150 as an “irresistible” antimalarial drug. However, the 50% cytotoxic concentration (CC50) of YAT2150 for human cells results in a relatively narrow therapeutic window. The perspectives of a successful clinical development of YAT2150 as an antimalarial drug will improve significantly if this therapeutic window can be widened. This can be achieved through a nanotechnological delivery strategy based on the encapsulation of YAT2150 in nanocarriers specifically targeted to Plasmodium-infected red blood cells. In this project YOU will design and evaluate new concepts to heighten this selectivity. Two strategies will be pursued: First will be assayed the synthesis of multivalent nanoparticles by the conjugation of YAT2150-based drugs to hyperbranched or arborescent polymers. These polymers offer up to hundreds of end-groups and the ability to adapt their conformation. The latter is a fundamental concept to leverage the multiple binding events with cooperative multivalency. The second strategy is the encapsulation in modern nanovesicles based on dendrimersomes. These vesicles can mimic natural cell membranes, display minimal cytotoxicity, and can be decorated with targeting elements. The project will be carried out jointly between the Bioinspired Interactive Materials and Protocellular Systems (BIMPS) and Nanomalaria groups at IBEC.
Job position description
We look for an enthusiastic, organized, and autonomous PhD candidate with a degree in Chemistry, Biology, Biochemistry, or similar areas. The thesis will be divided in 4 phases. During the first semester the candidate will investigate the free drugs and will become familiar with all necessary methods, including the in vitro culture of Plasmodium falciparum. In Phase 2, the candidate will design and synthesize the nanodrugs based on completely new hyperbranched polymers. The polymers will be selected to be stealth to host systems while enabling multivalency. Special effects such as molecular flexibility will be assessed by a combination of experimental and simulation approaches. In Phase 3, the fellow will characterize in P. falciparum in vitro cultures the viability of the pathogen and the level of protein aggregation in live parasite cells in response to treatment with the YAT2150 nanoformulations. Phases 2 and 3 will overlap and complement each other until the first semester of year 3. Finally, during the last semester of year 3, in vivo assays in malaria-infected mice will be performed, together with completion of all analyses, statistics, interpretation of results, and writing of the PhD Thesis. The results of the PhD will be publish in top journals and disseminated in international conferences. During the 3 years of the fellowship, the PhD fellow will acquire a strong knowledge of the cellular biology of P. falciparum through lab work, regular meetings with the PhD co-supervisors, bi-weekly journal clubs and weekly group meetings, and through daily readings of literature related to the field.
Specific requirements: Chemical synthesis, training in cell cultures, confocal fluorescence microscopy, genomic analysis, RNAseq and cellular and molecular biology techniques, experience with in vitro cultures of P. falciparum and the certificate for the manipulation of laboratory animals will be a plus.