Human Polo-like Kinase Inhibitors as Antiplasmodials.

  • Journal Article
  • Research Support, N.I.H., Extramural

ACS infectious diseases, Volume: 9, Issue: 4
April 14, 2023
Monica J Bohmer MJ, Jinhua Wang J, Eva S Istvan ES, Madeline R Luth MR, Jennifer E Collins JE, Edward L Huttlin EL, Lushun Wang L, Nimisha Mittal N, Mingfeng Hao M, Nicholas P Kwiatkowski NP, Steven P Gygi SP, Ratna Chakrabarti R, Xianming Deng X, Daniel E Goldberg DE, Elizabeth A Winzeler EA, Nathanael S Gray NS, Debopam Chakrabarti D

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 of cancer. Repurposing these inhibitors as antimalarials could provide an accelerated path to drug development. In this study, we identified BI-2536, a known potent human polo-like kinase 1 inhibitor, with low nanomolar antiplasmodial activity. Screening of additional PLK1 inhibitors revealed further antiplasmodial candidates despite the lack of an obvious orthologue of PLKs in . A subset of these inhibitors was profiled for their killing profile, and commonalities between the killing rate and inhibition of nuclear replication were noted. A kinase panel screen identified NEK3 as a shared target of these PLK1 inhibitors; however, phosphoproteome analysis confirmed distinct signaling pathways were disrupted by two structurally distinct inhibitors, suggesting NEK3 may not be the sole target. Genomic analysis of BI-2536-resistant parasites revealed mutations in genes associated with the starvation-induced stress response, suggesting BI-2536 may also inhibit an aminoacyl-tRNA synthetase.

Courtesy of the U.S. National Library of Medicine