ArticleThe Journal of infectious diseases2015
Diversity-oriented synthesis probe targets Plasmodium falciparum cytochrome b ubiquinone reduction site and synergizes with oxidation site inhibitors.
Article in The Journal of infectious diseases, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 23 papers.
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Who cites it
23 citing papers in PubMed.
- Article
- Towards next-generation treatment options to combat Plasmodium falciparum malaria.Nature reviews. Microbiology · 2025Review
- Article
- A screen of drug-like molecules identifies chemically diverse electron transport chain inhibitors in apicomplexan parasites.PLoS pathogens · 2023Article
- Advances in high-throughput mass spectrometry in drug discovery.EMBO molecular medicine · 2023Review
- MalDA, Accelerating Malaria Drug Discovery.Trends in parasitology · 2021Review
- Selection ofProceedings of the National Academy of Sciences of the United States of America · 2018Article
- Chemical probes and drug leads from advances in synthetic planning and methodology.Nature reviews. Drug discovery · 2018Review
- Using in Vitro Evolution and Whole Genome Analysis To Discover Next Generation Targets for Antimalarial Drug Discovery.ACS infectious diseases · 2018Review
- Characterization of the mechanism of action of the fungicide fenpicoxamid and its metabolite UK-2A.Pest management science · 2018Article
- Targeting Channels and Transporters in Protozoan Parasite Infections.Frontiers in chemistry · 2018Review
- Identification of Highly Specific Diversity-Oriented Synthesis-Derived Inhibitors of Clostridium difficile.ACS infectious diseases · 2017Article
- Discovery of Antimalarial Azetidine-2-carbonitriles That InhibitACS medicinal chemistry letters · 2017Article
- A Novel Methodology for Bioenergetic Analysis of Plasmodium falciparum Reveals a Glucose-Regulated Metabolic Shift and Enables Mode of Action Analyses of Mitochondrial Inhibitors.ACS infectious diseases · 2016Article
- Plasmodium falciparum Cyclic Amine Resistance Locus (PfCARL), a Resistance Mechanism for Two Distinct Compound Classes.ACS infectious diseases · 2016Article
- Article
- New paradigms for understanding and step changes in treating active and chronic, persistent apicomplexan infections.Scientific reports · 2016Article
- A broad analysis of resistance development in the malaria parasite.Nature communications · 2016Article
- High-throughput matrix screening identifies synergistic and antagonistic antimalarial drug combinations.Scientific reports · 2015Article
- Advancing Biological Understanding and Therapeutics Discovery with Small-Molecule Probes.Cell · 2015Review
Corrections and comments
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Authors and funding
16 authors.
Funding
Abstract
backgroundThe emergence and spread of drug resistance to current antimalarial therapies remains a pressing concern, escalating the need for compounds that demonstrate novel modes of action. Diversity-Oriented Synthesis (DOS) libraries bridge the gap between conventional small molecule and natural product libraries, allowing the interrogation of more diverse chemical space in efforts to identify probes of novel parasite pathways.
methodsWe screened and optimized a probe from a DOS library using whole-cell phenotypic assays. Resistance selection and whole-genome sequencing approaches were employed to identify the cellular target of the compounds.
resultsWe identified a novel macrocyclic inhibitor of Plasmodium falciparum with nanomolar potency and identified the reduction site of cytochrome b as its cellular target. Combination experiments with reduction and oxidation site inhibitors showed synergistic inhibition of the parasite.
conclusionsThe cytochrome b oxidation center is a validated antimalarial target. We show that the reduction site of cytochrome b is also a druggable target. Our results demonstrating a synergistic relationship between oxidation and reduction site inhibitors suggests a future strategy for new combination therapies in the treatment of malaria.
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