ArticleACS chemical biology2014
Assessing subunit dependency of the Plasmodium proteasome using small molecule inhibitors and active site probes.
Article in ACS chemical biology, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 37 papers, 1 of them a synthesis that pooled it.
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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.
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Who cites it
37 citing papers in PubMed, 1 synthesis or guideline pooled it, 55 citations in OpenAlex.
- Ubiquitin-proteasome system inFrontiers in medicine · 2024Pooled it
- Optimization of Species-Selective Reversible Proteasome Inhibitors for the Treatment of Malaria.Journal of medicinal chemistry · 2025Article
- Enhancing schistosomiasis drug discovery approaches with optimized proteasome substrates.Protein science : a publication of the Protein Society · 2025Article
- Carmaphycin B-Based Proteasome Inhibitors to Treat Human African Trypanosomiasis: Structure-Activity Relationship andACS infectious diseases · 2024Article
- Article
- The proteasome as a drug target for treatment of parasitic diseases.Advances in parasitology · 2024Review
- Proteasome inhibition as a therapeutic target for the fungal pathogenMicrobiology spectrum · 2023Article
- Identification of covalent fragment inhibitors for Plasmodium falciparum UCHL3 with anti-malarial efficacy.Bioorganic & medicinal chemistry letters · 2023Article
- Article
- Dual-pharmacophore artezomibs hijack the Plasmodium ubiquitin-proteasome system to kill malaria parasites while overcoming drug resistance.Cell chemical biology · 2023Article
- Structure-Activity Relationship Studies of AntimalarialJournal of medicinal chemistry · 2023Article
- Susceptibilities of Ugandan Plasmodium falciparum Isolates to Proteasome Inhibitors.Antimicrobial agents and chemotherapy · 2022Article
- Review
- Design, Synthesis, and Optimization of Macrocyclic Peptides as Species-Selective Antimalaria Proteasome Inhibitors.Journal of medicinal chemistry · 2022Article
- Targeting Proteasomes in Cancer and Infectious Disease: A Parallel Strategy to Treat Malignancies and Microbes.Frontiers in cellular and infection microbiology · 2022Review
- Microbial proteasomes as drug targets.PLoS pathogens · 2021Review
- Design of proteasome inhibitors with oral efficacy in vivo againstProceedings of the National Academy of Sciences of the United States of America · 2021Article
- Proteasome Inhibitors: Harnessing Proteostasis to Combat Disease.Molecules (Basel, Switzerland) · 2020Review
- Covalent Plasmodium falciparum-selective proteasome inhibitors exhibit a low propensity for generating resistance in vitro and synergize with multiple antimalarial agents.PLoS pathogens · 2019Article
- Target Validation and Identification of Novel Boronate Inhibitors of the Plasmodium falciparum Proteasome.Journal of medicinal chemistry · 2018Article
Corrections and comments
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Authors and funding
10 authors at 2 institutions in 2 countries.
Funding
Abstract
The ubiquitin-proteasome system (UPS) is a potential pathway for therapeutic intervention for pathogens such as Plasmodium, the causative agent of malaria. However, due to the essential nature of this proteolytic pathway, proteasome inhibitors must avoid inhibition of the host enzyme complex to prevent toxic side effects. The Plasmodium proteasome is poorly characterized, making rational design of inhibitors that induce selective parasite killing difficult. In this study, we developed a chemical probe that labels all catalytic sites of the Plasmodium proteasome. Using this probe, we identified several subunit selective small molecule inhibitors of the parasite enzyme complex. Treatment with an inhibitor that is specific for the β5 subunit during blood stage schizogony led to a dramatic decrease in parasite replication while short-term inhibition of the β2 subunit did not affect viability. Interestingly, coinhibition of both the β2 and β5 catalytic subunits resulted in enhanced parasite killing at all stages of the blood stage life cycle and reduced parasite levels in vivo to barely detectable levels. Parasite killing was achieved with overall low host toxicity, something that has not been possible with existing proteasome inhibitors. Our results highlight differences in the subunit dependency of the parasite and human proteasome, thus providing a strategy for development of potent antimalarial drugs with overall low host toxicity.
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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.