{"id":98505,"date":"2022-08-26T10:14:14","date_gmt":"2022-08-26T08:14:14","guid":{"rendered":"https:\/\/ibecbarcelona.eu\/?p=98505"},"modified":"2022-10-28T11:43:43","modified_gmt":"2022-10-28T09:43:43","slug":"predoctoral-researcher-at-the-nanomalaria-research-group","status":"publish","type":"post","link":"https:\/\/ibecbarcelona.eu\/es\/predoctoral-researcher-at-the-nanomalaria-research-group\/","title":{"rendered":"Predoctoral researcher at the Nanomalaria research group"},"content":{"rendered":"\n

Introduction to the vacant position:<\/strong><\/p>\n\n\n\n

The Nanomalaria <\/a>Group is looking for an Early Stage Researcher (PhD student) to develop his\/her PhD thesis project on the development of new antimalarial drugs. The contract will be within the framework of one of the research lines of the Nanomalaria Group, whose objective is the characterization of the inhibition of protein aggregation as a novel mode of action of future antimalarial drugs.<\/p>\n\n\n\n

The<\/a>  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<\/em>. This situation calls for immediate efforts to discover new compounds of easy and cost-affordable production, ideally belonging to chemical classes where no antimalarials have been described so far, having several molecular targets in the pathogen and acting through new mechanisms not shared by other currently used drugs. Although potentially toxic protein aggregates are abundant in all malaria parasite stages, the results of our current Plan Nacional<\/em> project indicate that peptides exacerbating protein aggregation in Plasmodium falciparum<\/em> do not affect its viability. However, in the same project we have obtained evidence that certain compounds inhibiting the aggregation of proteins are lethal for the pathogen at low nM concentrations. One such compound, the bis(styrylpyridinium) salt YAT2150, the active component of a commercial reagent used to stain protein deposits in live cells, was particularly attractive because of its easy, rapid and inexpensive synthesis and its activity against blood stages of P. falciparum<\/em>, with an in vitro<\/em> IC50 of 90 nM. This compound, a potent inhibitor of the aggregation of the amyloid \u03b2 peptide 1-40, presents no adverse effects in mice up to 10 mg\/kg and, because it fluoresces when in contact with Plasmodium<\/em>, it is a theranostic agent. <\/p>\n\n\n\n

The general objective of this project is to explore if the YAT2150-mediated inhibition of protein aggregation can be translated into an antimalarial strategy, which will be achieved through these detailed objectives: (i) to improve the selectivity index of YAT2150 through a targeted delivery strategy based on its encapsulation in immunoliposomes, (ii) to characterize in live Plasmodium<\/em> cells the role of YAT2150 as protein aggregation inhibitor in both asexual blood stages and in sexual (gametocyte) forms, (iii) to assess the likelihood of resistance evolution in Plasmodium<\/em> to YAT2150, and (iv) to determine the in vivo<\/em> antimalarial activity of YAT2150. The results of these concrete objectives will inform about the overarching question of which is the physiological role of protein aggregation in malaria parasites. Because impairing proteostasis potentially targets multiple gene products, rapid evolution of resistance to this drug is unlikely to occur. In addition, YAT2150 belongs to a chemical family where no antimalarials have been described so far, and therefore the parasite will not be able to adapt resistance mechanisms already existing for other drugs. <\/p>\n\n\n\n

The results of the characterization of the in vitro<\/em> activity of the liposome-encapsulated drug, the study of its antimalarial mechanism, and the assessment of its in vivo<\/em> activity and of the likelihood of the evolution of resistances to it, will be determinant to decide if YAT2150 can enter the preclinical and clinical pipeline leading to its development into a new antimalarial medicine. Taking into account the economic landscape of malaria, certain properties of YAT2150 (high activity against Plasmodium<\/em> blood stages, relatively low in vivo<\/em> toxicity, belonging to a new family of antimalarials, cost-efficient synthesis and storage at room temperature for long periods of time), present it as a potentially key actor regarding future efforts leading to malaria eradication.<\/p>\n\n\n\n

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<\/a><\/p>\n\n\n\n

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Main tasks and responsibilities \/ The successful candidate will develop research involving:<\/strong><\/p>\n\n\n\n