Discovery of potent inhibitors of Plasmodium PK5

Abstract

<p>Malaria is one of the oldest and deadliest diseases in the world, affecting approximately 200 million people annually. The role of protein phosphorylation in the complex life cycle of the malaria parasite, Plasmodium, as well as the promising therapeutic values of protein kinase inhibitors have sparked increasing interest in understanding the Plasmodium kinome. Although many protein kinases have been shown to be essential for Plasmodium survival, their functions remain unknown. Protein kinase 5 (PK5) is a putative cyclin dependent kinase (CDK)-like protein in the malaria parasite, and it is thought to be essential for blood stage proliferation in P. falciparum. In the present study, biochemical binding assays were used to identify potent and selective inhibitors of PfPK5. Two compounds were found to selectively bind to PfPK5 over the human analog, Homo sapiens CDK2. In addition, a known CDK inhibitor was used in the development of a chemical probe to identify potential macromolecules essential to parasite survival. Here, we report important structural moieties potentially involved in PfPK5 binding. Elucidation of the biological targets through the use of our chemical probe may aid in further understanding of Plasmodium biology.</p>