ArticleCell chemical biology2023
Mitigating the risk of antimalarial resistance via covalent dual-subunit inhibition of the Plasmodium proteasome.
Article in Cell chemical biology, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 19 papers, 1 of them a synthesis that pooled it.
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Who cites it
19 citing papers in PubMed, 1 synthesis or guideline pooled it, 22 citations in OpenAlex.
- Ubiquitin-proteasome system inFrontiers in medicine · 2024Pooled it
- Dual plasmepsin IX and X inhibitors are refractory to development of resistance.PLoS pathogens · 2026Article
- Plasmodium falciparum HSP90 inhibitors show divergent resistance despite a shared ATP-binding site.Cell reports · 2026Article
- Minimum Inoculum of Resistance Assay for Evaluating Antitoxoplasmosis Compounds That Target Phenylalanine tRNA Synthetase.ACS infectious diseases · 2026Article
- Structure-Guided Optimization of Novel Inhibitors ofJournal of medicinal chemistry · 2026Article
- CAR-macrophage therapy: a novel strategy to overcome antimalarial drug resistance by targeting PfEMP1-mediated adhesion.Malaria journal · 2026Article
- Minimum inoculum of resistance assay for evaluating for anti-toxoplasmosis compounds that target phenyl alanine tRNA synthetase.bioRxiv : the preprint server for biology · 2026Article
- Shared Binding Site but Divergent Resistance Profiles Uncover Novel Resistance Mechanisms inbioRxiv : the preprint server for biology · 2025Article
- A recombinant expression system for thebioRxiv : the preprint server for biology · 2025Article
- Towards next-generation treatment options to combat Plasmodium falciparum malaria.Nature reviews. Microbiology · 2025Review
- Enhanced cell stress response and protein degradation capacity underlie artemisinin resistance inmSphere · 2024Article
- Identification of potent and reversible piperidine carboxamides that are species-selective orally active proteasome inhibitors to treat malaria.Cell chemical biology · 2024Article
- tRNA modification reprogramming contributes to artemisinin resistance in Plasmodium falciparum.Nature microbiology · 2024Article
- Recent advances of phenotypic screening strategies in the application of anti-influenza virus drug discovery.RSC medicinal chemistry · 2024Review
- Article
- Structures revealing mechanisms of resistance and collateral sensitivity of Plasmodium falciparum to proteasome inhibitors.Nature communications · 2023Article
- Covalent Macrocyclic Proteasome Inhibitors Mitigate Resistance inACS infectious diseases · 2023Article
- Antimalarial drug discovery: progress and approaches.Nature reviews. Drug discovery · 2023Review
- Parasite proteostasis and artemisinin resistance.Research square · 2023Article
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Authors and funding
26 authors at 12 institutions in 4 countries.
Funding
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.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.