In the human disease-causing agent, Plasmodium falciparum, our understanding of signaling pathways remains limited and there exists a paucity of pharmacological tools to interrogate biology. Among Plasmodium’s protein kinases, those defined as atypical have sequences distinct from any protein in their human host, making their function particularly elusive. Here, we describe the discovery of novel small molecules that bind to the active site of the atypical kinase P. falciparum protein kinase 9 (PfPK9) from a chemoproteomic screen. Analysis of the screening hits and subsequent biochemical studies revealed structural similarity between the ATP-binding site of PfPK9 and human kinases involved in ubiquitination signaling pathways. Importantly, the use of PK9 inhibitors as chemical probes suggests the existence of an unexplored yet essential ubiquitin signaling pathway in Plasmodium parasites.

A chemical biology approach reveals ubiquitin signaling in Plasmodium

254th National Meeting (2017)

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