Selective targeting of Plasmodium falciparum Hsp90 disrupts the 26S proteasome.

TitleSelective targeting of Plasmodium falciparum Hsp90 disrupts the 26S proteasome.
Publication TypeJournal Article
Year of Publication2024
AuthorsMansfield CR, Quan B, Chirgwin ME, Eduful B, Hughes PF, Neveu G, Sylvester K, Ryan DH, Kafsack BFC, Haystead TAJ, Leahy JW, Fitzgerald MC, Derbyshire ER
JournalCell Chem Biol
Volume31
Issue4
Pagination729-742.e13
Date Published2024 Apr 18
ISSN2451-9448
KeywordsAntimalarials, HSP90 Heat-Shock Proteins, Molecular Chaperones, Plasmodium falciparum, Proteasome Endopeptidase Complex, Proteome
Abstract

The molecular chaperone heat shock protein 90 (Hsp90) has an essential but largely undefined role in maintaining proteostasis in Plasmodium falciparum, the most lethal malaria parasite. Herein, we identify BX-2819 and XL888 as potent P. falciparum (Pf)Hsp90 inhibitors. Derivatization of XL888's scaffold led to the development of Tropane 1, as a PfHsp90-selective binder with nanomolar affinity. Hsp90 inhibitors exhibit anti-Plasmodium activity against the liver, asexual blood, and early gametocyte life stages. Thermal proteome profiling was implemented to assess PfHsp90-dependent proteome stability, and the proteasome-the main site of cellular protein recycling-was enriched among proteins with perturbed stability upon PfHsp90 inhibition. Subsequent biochemical and cellular studies suggest that PfHsp90 directly promotes proteasome hydrolysis by chaperoning the active 26S complex. These findings expand our knowledge of the PfHsp90-dependent proteome and protein quality control mechanisms in these pathogenic parasites, as well as further characterize this chaperone as a potential antimalarial drug target.

DOI10.1016/j.chembiol.2024.02.008
Alternate JournalCell Chem Biol
PubMed ID38492573
PubMed Central IDPMC11031320
Grant ListR01 AI173295 / AI / NIAID NIH HHS / United States
T32 GM008555 / GM / NIGMS NIH HHS / United States

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