Last Updated: 07/10/2025
Research into protein aggregation as a new antimalarial target
Objectives
The objective of this proposal is to investigate the effect of endogenous aggregative peptides on Plasmodium and their trafficking between parasitized erythrocytes, forming the foundation for a novel antimalarial approach.
Specific objectives:
- Selection and characterization of aggregative peptides present in Plasmodium;
- Evaluation of the toxicity of endogenous aggregative peptides to Plasmodium; and
- Exploration of peptide transfer between malaria parasites via extracellular vesicles.
Despite the importance of malaria elimination on the global health agenda, current drugs are rapidly losing their effectiveness due to the evolution of resistance in the parasite that causes the disease, Plasmodium sp. Therefore, alternative antimalarial strategies based on innovative therapeutic principles are urgently needed.
Throughout three previous projects funded by this program, the research team developed an initial immunoliposomal prototype loaded with antimalarials and vectorized toward erythrocytes infected by Plasmodium. This prototype has since been refined, adapting the encapsulator and vector elements to different therapeutic approaches, encapsulated compounds, and target cells.
In this project, the investigators propose to continue this adaptation by incorporating the study of a potential new antimalarial mechanism: protein aggregation. Proteins with extensive low-complexity regions enriched in glutamine/asparagine (Q/N) are prone to form insoluble intracellular aggregates that can lead to cell death through the propagation of aberrant interactions. In most species, proteins with Q/N-rich regions account for less than 1% of the proteome; however, in Plasmodium falciparum, this proportion rises to 30% across all protein families and developmental stages.
Previous studies in bacteria have shown that the cytotoxicity of protein aggregation can be harnessed to eliminate pathogens without harming the mammalian host, supporting the hypothesis that controlled protein aggregation could represent a new antimicrobial strategy against Plasmodium and other parasites.
The researchers anticipate that the results from this work could eventually enable the design of new malaria therapies based on the parasite’s own proteostatic vulnerability—either (i) by inducing uncontrolled aggregation of its proteome to trigger toxicity, or (ii) by inhibiting aggregation if this process proves essential for parasite survival.
To achieve this, the team will utilize nanotechnology tools developed in their laboratory for vectorized drug delivery, including the encapsulation of protein aggregation primer peptides in immunoliposomes and chitosan/heparin polymeric nanoparticles. Both intraerythrocytic blood stages and ookinetes—the stage present in the mosquito vector—will be investigated as target cells. This final step will also serve as groundwork for potential future strategies aimed at delivering transmission-blocking drugs directly to mosquitoes.
By targeting Plasmodium’s proteostatic machinery, the investigators aim to disrupt multiple essential gene products simultaneously, thereby significantly reducing the likelihood of resistance development.
Jan 2018
$142,782
Related Resources
