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- W4360610819 abstract "The Plasmodium falciparum proteasome constitutes a promising antimalarial target, with multiple chemotypes potently and selectively inhibiting parasite proliferation and synergizing with the first-line artemisinin drugs, including against artemisinin-resistant parasites. We compared resistance profiles of vinyl sulfone, epoxyketone, macrocyclic peptide, and asparagine ethylenediamine inhibitors and report that the vinyl sulfones were potent even against mutant parasites resistant to other proteasome inhibitors and did not readily select for resistance, particularly WLL that displays covalent and irreversible binding to the catalytic β2 and β5 proteasome subunits. We also observed instances of collateral hypersensitivity, whereby resistance to one inhibitor could sensitize parasites to distinct chemotypes. Proteasome selectivity was confirmed using CRISPR/Cas9-edited mutant and conditional knockdown parasites. Molecular modeling of proteasome mutations suggested spatial contraction of the β5 P1 binding pocket, compromising compound binding. Dual targeting of P. falciparum proteasome subunits using covalent inhibitors provides a potential strategy for restoring artemisinin activity and combating the spread of drug-resistant malaria." @default.
- W4360610819 created "2023-03-24" @default.
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- W4360610819 date "2023-05-01" @default.
- W4360610819 modified "2023-10-15" @default.
- W4360610819 title "Mitigating the risk of antimalarial resistance via covalent dual-subunit inhibition of the Plasmodium proteasome" @default.
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- W4360610819 doi "https://doi.org/10.1016/j.chembiol.2023.03.002" @default.
- W4360610819 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/36963402" @default.
- W4360610819 hasPublicationYear "2023" @default.