ArticleJournal of the American Chemical Society2018
Defining the Determinants of Specificity of Plasmodium Proteasome Inhibitors.
Article in Journal of the American Chemical Society, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 42 papers.
What it found
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Who cites it
42 citing papers in PubMed, 63 citations in OpenAlex.
- Structure-Activity Relationship Study of Antimalarial Asparagine-Derived Proteasome Inhibitors.ACS omega · 2026Article
- Targeting protein-protein interactions in Plasmodium: from asexual replication to sexual development.Parasites & vectors · 2026Review
- A recombinant expression system for thebioRxiv : the preprint server for biology · 2025Article
- Enhancing schistosomiasis drug discovery approaches with optimized proteasome substrates.Protein science : a publication of the Protein Society · 2025Article
- Emerging opportunities for intact and native protein analysis using chemical proteomics.Analytica chimica acta · 2025Review
- Structural comparison of human and Plasmodium proteasome β5 subunits: informing selective inhibitor design for anti-malaria agents.Malaria journal · 2025Article
- Identification of potent and reversible piperidine carboxamides that are species-selective orally active proteasome inhibitors to treat malaria.Cell chemical biology · 2024Article
- Discovery of a Tunable Heterocyclic Electrophile 4-Chloro-pyrazolopyridine That Defines a Unique Subset of Ligandable Cysteines.ACS chemical biology · 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
- Identification of covalent fragment inhibitors for Plasmodium falciparum UCHL3 with anti-malarial efficacy.Bioorganic & medicinal chemistry letters · 2023Article
- Generation of a mutator parasite to drive resistome discovery in Plasmodium falciparum.Nature communications · 2023Article
- Dual-pharmacophore artezomibs hijack the Plasmodium ubiquitin-proteasome system to kill malaria parasites while overcoming drug resistance.Cell chemical biology · 2023Article
- Mitigating the risk of antimalarial resistance via covalent dual-subunit inhibition of the Plasmodium proteasome.Cell chemical biology · 2023Article
- Development of Potent and Highly Selective Epoxyketone-Based Plasmodium Proteasome Inhibitors.Chemistry (Weinheim an der Bergstrasse, Germany) · 2023Article
- Structure-Activity Relationship Studies of AntimalarialJournal of medicinal chemistry · 2023Article
- New targets for antimalarial drug discovery.Current opinion in microbiology · 2022Review
- Susceptibilities of Ugandan Plasmodium falciparum Isolates to Proteasome Inhibitors.Antimicrobial agents and chemotherapy · 2022Article
Corrections and comments
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Authors and funding
13 authors at 4 institutions in 2 countries.
Funding
Abstract
The Plasmodium proteasome is an emerging antimalarial target due to its essential role in all the major life cycle stages of the parasite and its contribution to the establishment of resistance to artemisinin (ART)-based therapies. However, because of a similarly essential role for the host proteasome, the key property of any antiproteasome therapeutic is selectivity. Several parasite-specific proteasome inhibitors have recently been reported, however, their selectivity must be improved to enable clinical development. Here we describe screening of diverse libraries of non-natural synthetic fluorogenic substrates to identify determinants at multiple positions on the substrate that produce enhanced selectivity. We find that selection of an optimal electrophilic "warhead" is essential to enable high selectivity that is driven by the peptide binding elements on the inhibitor. We also find that host cell toxicity is dictated by the extent of coinhibition of the human β2 and β5 subunits. Using this information, we identify compounds with over 3 orders of magnitude selectivity for the parasite enzyme. Optimization of the pharmacological properties resulted in molecules that retained high potency and selectivity, were soluble, sufficiently metabolically stable and orally bioavailable. These molecules are highly synergistic with ART and can clear parasites in a mouse model of infection, making them promising leads as antimalarial 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.