Using genetic methods to define the targets of compounds with antimalarial activity

Area of Science:

• Malariology
• Drug Discovery
• Genomics

Background:

• Phenotypic cellular screening is common in antimalarial drug discovery.
• Target-based discovery is preferred when high-throughput cellular assays are lacking, such as for primaquine replacements.
• Currently, no validated Plasmodium targets exist for all parasite stages suitable for biochemical screens.

Purpose of the Study:

• To highlight the potential for discovering novel, chemically validated, cross-stage antimalarial targets.
• To propose a method for identifying targets of compounds found through phenotypic screening.

Main Methods:

• In vitro evolution of drug-resistant Plasmodium falciparum strains.
• Whole-genome analysis of resistant strains.

Main Results:

• The study discusses the potential of the proposed methods to identify novel drug targets.
• It emphasizes the vast number of undiscovered targets within the Plasmodium proteome.

Conclusions:

• Novel antimalarial drug targets can be discovered by combining phenotypic screening with genomic approaches.
• In vitro evolution coupled with whole-genome analysis offers a viable strategy to identify targets for compounds identified in cellular screens.