Chemoproteomic profiling of Plasmodium falciparum Hsp90 inhibition reveals functional link to DNA replication pathways
Plasmodium falciparum heat shock protein 90 (PfHsp90) is a promising antimalarial target, but the molecular pathways influenced by its inhibition remain poorly understood. Herein, we leveraged chemoproteomic profiling employing geldanamycin and XL888 Hsp90 inhibitors to investigate proteins and pathways dependent on the chaperone during the Plasmodium blood stage. This study revealed 131 proteins…
A recent study explores the impact of inhibiting Plasmodium falciparum heat shock protein 90 (PfHsp90), a promising antimalarial target. Researchers employed chemoproteomic profiling using geldanamycin and XL888 Hsp90 inhibitors to investigate the proteins and pathways affected by PfHsp90 inhibition during the Plasmodium blood stage.
The study identified 131 proteins whose abundance decreased following inhibitor treatment, with 40% co-immunoprecipitating with PfHsp90. Bioinformatic analyses revealed DNA replication as the most enriched pathway linked to PfHsp90 inhibition. This connection was further investigated through phenotypic studies, which demonstrated reduced parasite DNA content after PfHsp90 inhibition.
To examine the effects on DNA synthesis, a 7-deaza-7-ethynyl-2-deoxyadenosine (EdA) assay was used, revealing dual-stage attenuation of nucleoside incorporation following Hsp90 inhibition. Additionally, co-treatment of parasites with Hsp90 and DNA replication inhibitors showed synergistic interactions, suggesting potential therapeutic benefits.
This research expands our understanding of PfHsp90 function and uncovers novel PfHsp90-dependent pathways.
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