Last Updated: 15/10/2025
New antimalarial therapies targeting glycosylation pathways of Plasmodium falciparum (GlycoTargets)
Objectives
This study through virtual screening based on 3D structure predictions and CRISPR-CAS9-mediated genetic engineering, will chemically and genetically validate the three aforementioned pathways (hexosamine (HBP) biosynthesis pathway, glycosylphosphatidylinositol (GPI) biosynthesis, and N-glycosylation) as drug targets for the design of new antiplasmadic agents. This study propose to focus on identifying new compounds capable of halting parasite growth by inhibiting these pathways. In short, the researcher will pursue a basic research approach with the goal of identifying much-needed molecules capable of eliminating the malaria parasite through novel mechanisms of action.
Malaria is a serious global health problem that kills more than 600,000 people each year, primarily children under five years of age and pregnant women in sub-Saharan Africa. Plasmodium falciparum causes the most severe form of malaria and is the species responsible for the largest number of deaths. Malaria is a preventable and curable disease, and artemisinin-based combination therapies are one of the main tools for its control. However, the extraordinary metabolic plasticity of P. falciparum makes the parasite prone to developing resistance to any and all treatments discovered. In fact, artemisinin resistance is beginning to emerge in the Greater Mekong subregion, underscoring the urgent need to develop new tools and therapies to combat the disease. Recent results from the principal investigator’s laboratory and other research groups confirm that glycoconjugates play fundamental roles in the development of P. falciparum. In fact, according to data from various sources, the parasite appears to be particularly sensitive to disruptions in these glycosylation mechanisms.The hypothesis of this study is that certain glycosylation pathways, namely the hexosamine (HBP) biosynthesis pathway, glycosylphosphatidylinositol (GPI) biosynthesis, and N-glycosylation, could be excellent unexplored targets for developing new strategies to halt parasite growth. HBP is a side pathway of glycolysis that generates uridine diphosphate-N-acetylglucosamine (UDP-GLCNAC), a nucleotide sugar essential for the development of the asexual parasite and involved in the biosynthesis of GPI anchors and N-glycans. GPI are the most prominent form of protein glycosylation in P. falciparum and anchor essential proteins to the surface of the parasite throughout the different stages of its life cycle. Finally, N-glycosylation is an essential process in most eukaryotes that takes place in the endoplasmic reticulum and modulates the folding, stability, trafficking, and function of proteins expressed in the secretory pathway. The researcher’s recent results indicate that N-glycosylation is active and essential for the survival of P. falciparum in its intraerythrocyte asexual stages. Surprisingly, parasites with altered N-glycosylation display a peculiar “delayed death” phenotype, in which they do not stop replicating until the second cycle after the alteration. In particular, delayed death has been previously described in P. falciparum in association with apicoplast-targeted inhibitors. The unexpected relationship between N-glycosylation and delayed death raises new and interesting questions that deserve in-depth exploration due to their importance for the biology and survival of the parasite.
Sep 2024 — Aug 2026
$260,225
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