Targeting Aurora Kinases as Essential Cell-Cycle Regulators to Deliver Multi-Stage Antimalarials Against Plasmodium...

Area of Science:

• Parasitology
• Molecular Biology
• Drug Discovery

Background:

• Kinases are crucial for Plasmodium falciparum development and adaptation.
• Mitotic kinases regulate parasite proliferation by controlling nuclear division and cytokinesis.
• Targeting these kinases presents opportunities for novel antimalarial chemotherapeutics.

Purpose of the Study:

• To evaluate human Aurora kinase (Aur) inhibitors for their potential to inhibit Plasmodium falciparum development.
• To investigate the targeting of Aurora-related kinase (Ark) family members in P. falciparum.
• To identify specific targets for antimalarial drug development.

Main Methods:

• Screening of human Aurora kinase inhibitors against P. falciparum.
• Assessing compound potency across various proliferative stages of the parasite.
• Determining the selectivity of potent compounds towards P. falciparum over human kinases.
• Identifying the specific P. falciparum Ark family member targeted by hesperadin.

Main Results:

• Several human AurB inhibitors demonstrated potent, multistage activity (< 250 nM) against P. falciparum.
• Hesperadin, TAE684, and AT83 showed high selectivity (>1000x) for the parasite.
• PfArk1 was identified as the primary vulnerable Ark family member, with hesperadin specifically inhibiting it.
• Inhibition of PfArk1 led to defects in mitotic processes, including unsegregated nuclei and aberrant microtubule organization.

Conclusions:

• PfArk1 functions as the main Aurora mitotic kinase in proliferative stages of Plasmodium, exhibiting bifunctional AurA and B activity.
• Hesperadin is a potent and selective PfArk1 inhibitor, validating its utility as a tool compound.
• Targeting PfArk1 with hesperadin-based drug discovery offers a promising strategy for developing new antimalarial therapies.