Targeting protein-protein interactions in Plasmodium: from asexual replication to sexual development

Area of Science:

• Parasitology
• Structural Biology
• Drug Discovery

Background:

• Malaria remains a critical global health issue, with millions affected annually.
• Insecticide and drug resistance in Plasmodium parasites severely hinders malaria control efforts.
• Conventional antimalarials targeting enzyme sites are prone to resistance; targeting protein-protein interactions (PPIs) presents a more robust alternative due to their lower mutational potential.

Purpose of the Study:

• To review structural and functional data on key Plasmodium multi-subunit complexes.
• To evaluate therapeutic and transmission-blocking strategies targeting protein-protein interactions (PPIs).
• To highlight PPIs as promising targets for next-generation antimalarials.

Main Methods:

• Systematic synthesis of recent structural and functional advances in Plasmodium complexes.
• Integration of cryo-electron microscopy and proximity-dependent biotinylation data.
• Evaluation of genetic manipulation techniques and PPI-targeted intervention strategies.

Main Results:

• Detailed architecture and druggable vulnerabilities of asexual-stage PPI networks identified (e.g., invasion, nutrient uptake, egress).
• Dissection of PPI networks crucial for sexual development and mosquito transmission.
• Summary of preclinical and clinical progress for PPI-targeted therapies, including antibodies and small molecules.

Conclusions:

• Targeting Plasmodium PPI interfaces is a resilient strategy against antimalarial resistance.
• Technological advancements are making previously "undruggable" PPI targets accessible.
• PPI-targeting offers significant potential for malaria elimination by overcoming drug resistance.