ArticlePLoS pathogens2019
Covalent Plasmodium falciparum-selective proteasome inhibitors exhibit a low propensity for generating resistance in vitro and synergize with multiple antimalarial agents.
Article in PLoS pathogens, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 54 papers, 1 of them a synthesis that pooled it.
What it found
Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.
The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
54 citing papers in PubMed, 1 synthesis or guideline pooled it, 81 citations in OpenAlex.
- Ubiquitin-proteasome system inFrontiers in medicine · 2024Pooled it
- New thinking for the next generation of antimalarials.EMBO molecular medicine · 2026Review
- Article
- Combating Malaria: Targeting the Ubiquitin-Proteasome System to Conquer Drug Resistance.Tropical medicine and infectious disease · 2025Review
- Towards next-generation treatment options to combat Plasmodium falciparum malaria.Nature reviews. Microbiology · 2025Review
- Malaria parasite cysteine and aspartic proteases as key drug targets for antimalarial therapy.Journal of molecular modeling · 2025Review
- The essential genome ofScience (New York, N.Y.) · 2025Article
- YAT2150 is irresistible in Plasmodium falciparum and active against Plasmodium vivax and Leishmania clinical isolates.Scientific reports · 2025Article
- Systematic in vitro evolution inScience (New York, N.Y.) · 2024Article
- Enhanced cell stress response and protein degradation capacity underlie artemisinin resistance inmSphere · 2024Article
- TargetingJournal of medicinal chemistry · 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
- Mutation in the 26S proteasome regulatory subunitFrontiers in cellular and infection microbiology · 2024Article
- The proteasome as a drug target for treatment of parasitic diseases.Advances in parasitology · 2024Review
- 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
- Article
- High-content imaging as a tool to quantify and characterize malaria parasites.Cell reports methods · 2023Article
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
10 authors at 4 institutions in 2 countries.
Funding
Abstract
Therapeutics with novel modes of action and a low risk of generating resistance are urgently needed to combat drug-resistant Plasmodium falciparum malaria. Here, we report that the peptide vinyl sulfones WLL-vs (WLL) and WLW-vs (WLW), highly selective covalent inhibitors of the P. falciparum proteasome, potently eliminate genetically diverse parasites, including K13-mutant, artemisinin-resistant lines, and are particularly active against ring-stage parasites. Selection studies reveal that parasites do not readily acquire resistance to WLL or WLW and that mutations in the β2, β5 or β6 subunits of the 20S proteasome core particle or in components of the 19S proteasome regulatory particle yield only <five-fold decreases in parasite susceptibility. This result compares favorably against previously published non-covalent inhibitors of the Plasmodium proteasome that can select for resistant parasites with >hundred-fold decreases in susceptibility. We observed no cross-resistance between WLL and WLW. Moreover, most mutations that conferred a modest loss of parasite susceptibility to one inhibitor significantly increased sensitivity to the other. These inhibitors potently synergized multiple chemically diverse classes of antimalarial agents, implicating a shared disruption of proteostasis in their modes of action. These results underscore the potential of targeting the Plasmodium proteasome with covalent small molecule inhibitors as a means of combating multidrug-resistant malaria.
Indexed as
Identifiers
What OpenQuestion holds
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.