Human Polo-like Kinase Inhibitors as Antiplasmodials.

Area of Science:

• Medicinal Chemistry
• Parasitology
• Drug Discovery

Background:

• Protein kinase inhibitors are successful cancer therapeutics.
• Repurposing kinase inhibitors offers a faster route to antimalarial drug development.
• Polo-like kinases (PLKs) are validated cancer targets, but their role in Plasmodium is unclear.

Purpose of the Study:

• To identify and characterize novel antimalarial compounds from existing kinase inhibitor libraries.
• To investigate the mechanism of action of identified antimalarials.
• To explore potential off-target effects and resistance mechanisms.

Main Methods:

• Screening of human polo-like kinase 1 (PLK1) inhibitors for antiplasmodial activity.
• In vitro killing assays and assessment of nuclear replication inhibition.
• Kinase panel screening and phosphoproteome analysis.
• Genomic analysis of drug-resistant parasites.

Main Results:

• BI-2536, a PLK1 inhibitor, exhibited potent low nanomolar antiplasmodial activity.
• Several other PLK1 inhibitors also showed antimalarial potential.
• PfNEK3 was identified as a potential target, but distinct signaling disruptions suggest multiple targets.
• Resistance analysis implicated aminoacyl-tRNA synthetase inhibition by BI-2536.

Conclusions:

• PLK1 inhibitors represent a promising class of compounds for antimalarial drug development.
• The antiplasmodial mechanism is complex, potentially involving PfNEK3 and other targets like aminoacyl-tRNA synthetase.
• Further investigation is warranted to fully elucidate the therapeutic potential and resistance mechanisms.