Human Polo-like Kinase Inhibitors as Antiplasmodials

• DOI: 10.1021/acsinfecdis.3c00025
• Publication Date: 2023-03-15T11:42:10Z
• Authors: Monica J. Bohmer; Jinhua Wang; Eva S. Istvan; Madeline R. Luth; Jennifer E. Collins; Edward L. Huttlin; Lushun Wang; Nimisha Mittal; Mingfeng Hao; Nicholas P. Kwiat...; Steven P. Gygi; Ratna Chakrabarti; Xianming Deng; Daniel E. Goldberg; Elizabeth A. Winz...; Nathanael S. Gray; Debopam Chakrabarti
• Keywords: PLK1; Polo-like kinase; Drug repositioning; Drug Development; Repurposing

Protein kinases have proven to be a very productive class of therapeutic targets, and over 90 inhibitors are currently in clinical use primarily for the treatment cancer. Repurposing these as antimalarials could provide an accelerated path drug development. In this study, we identified BI-2536, known potent human polo-like kinase 1 inhibitor, with low nanomolar antiplasmodial activity. Screening additional PLK1 revealed further candidates despite lack obvious orthologue PLKs Plasmodium. A subset was profiled their vitro killing profile, commonalities between rate inhibition nuclear replication were noted. panel screen PfNEK3 shared target inhibitors; however, phosphoproteome analysis confirmed distinct signaling pathways disrupted by two structurally inhibitors, suggesting may not sole target. Genomic BI-2536-resistant parasites mutations genes associated starvation-induced stress response, BI-2536 also inhibit aminoacyl-tRNA synthetase.