ArticleChemistry (Weinheim an der Bergstrasse, Germany)2023
Development of Potent and Highly Selective Epoxyketone-Based Plasmodium Proteasome Inhibitors.
Article in Chemistry (Weinheim an der Bergstrasse, Germany), 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers, 1 of them a synthesis that pooled it.
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Who cites it
16 citing papers in PubMed, 1 synthesis or guideline pooled it, 21 citations in OpenAlex.
- Ubiquitin-proteasome system inFrontiers in medicine · 2024Pooled it
- Structure-Activity Relationship Study of Antimalarial Asparagine-Derived Proteasome Inhibitors.ACS omega · 2026Article
- Inhibitors of the 20S proteasome β5 subunit as potent and selective agents againstAntimicrobial agents and chemotherapy · 2025Article
- A recombinant expression system for thebioRxiv : the preprint server for biology · 2025Article
- In Silico Design and Analysis of Cyanobacterial Pseudo Natural Products.Journal of natural products · 2025Article
- Enhancing schistosomiasis drug discovery approaches with optimized proteasome substrates.Protein science : a publication of the Protein Society · 2025Article
- Cyanobacterial Peptides in Anticancer Therapy: A Comprehensive Review of Mechanisms, Clinical Advances, and Biotechnological Innovation.Marine drugs · 2025Review
- Carmaphycin B-Based Proteasome Inhibitors to Treat Human African Trypanosomiasis: Structure-Activity Relationship andACS infectious diseases · 2024Article
- Distinct substrate specificities of the three catalytic subunits of the Trichomonas vaginalis proteasome.Protein science : a publication of the Protein Society · 2024Article
- Evaluating Antimalarial Proteasome Inhibitors for Efficacy inACS omega · 2024Article
- Structural elucidation of recombinant Trichomonas vaginalis 20S proteasome bound to covalent inhibitors.Nature communications · 2024Article
- Identification of potent and reversible piperidine carboxamides that are species-selective orally active proteasome inhibitors to treat malaria.Cell chemical biology · 2024Article
- Macrocyclic Oxindole Peptide Epoxyketones-A Comparative Study of Macrocyclic Inhibitors of the 20S Proteasome.ACS medicinal chemistry letters · 2024Article
- The proteasome as a drug target for treatment of parasitic diseases.Advances in parasitology · 2024Review
- Antimalarial drug discovery: progress and approaches.Nature reviews. Drug discovery · 2023Review
- Mitigating the risk of antimalarial resistance via covalent dual-subunit inhibition of the Plasmodium proteasome.Cell chemical biology · 2023Article
Corrections and comments
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Authors and funding
15 authors at 5 institutions in 4 countries.
Funding
Abstract
Here, we present remarkable epoxyketone-based proteasome inhibitors with low nanomolar in vitro potency for blood-stage Plasmodium falciparum and low cytotoxicity for human cells. Our best compound has more than 2,000-fold greater selectivity for erythrocytic-stage P. falciparum over HepG2 and H460 cells, which is largely driven by the accommodation of the parasite proteasome for a D-amino acid in the P3 position and the preference for a difluorobenzyl group in the P1 position. We isolated the proteasome from P. falciparum cell extracts and determined that the best compound is 171-fold more potent at inhibiting the β5 subunit of P. falciparum proteasome when compared to the same subunit of the human constitutive proteasome. These compounds also significantly reduce parasitemia in a P. berghei mouse infection model and prolong survival of animals by an average of 6 days. The current epoxyketone inhibitors are ideal starting compounds for orally bioavailable anti-malarial drugs.
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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.