ArticleJournal of cell science2016
Haemoglobin degradation underpins the sensitivity of early ring stage Plasmodium falciparum to artemisinins.
Article in Journal of cell science, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 64 papers.
What it found
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Who cites it
64 citing papers in PubMed, 114 citations in OpenAlex.
- Collateral hypersensitivity between ZY19489 and piperaquine neutralizes PfCRT-mediated drug efflux and Plasmodium falciparum resistance.Nature communications · 2026Article
- Safeguarding artemisinin: integrating bioproduction innovation and resistance management for malaria eradication.Malaria journal · 2025Review
- Evolutionary Trajectory ofBiomedicines · 2025Review
- Epigenetically conferred ring-stage survival in Plasmodium falciparum against artemisinin treatment.Nature communications · 2025Article
- Identifying a next-generation antimalarial trioxolane in a landscape of artemisinin partial resistance.Science advances · 2025Article
- Single-cell transcriptional changes across the blood stages of artemisinin-resistant K13bioRxiv : the preprint server for biology · 2025Article
- PI3-kinase has multiple functions in asexual blood stages of Plasmodium falciparum.Scientific reports · 2025Article
- Vesicular mechanisms of drug resistance in apicomplexan parasites.Microbiology and molecular biology reviews : MMBR · 2025Review
- Artemisinin pressure in field isolates can select highly resistantAntimicrobial agents and chemotherapy · 2025Article
- The essential genome ofScience (New York, N.Y.) · 2025Article
- Stage-specific pharmacodynamic chloroquine and pyronaridine action on artemisinin ring-stage resistant Kelch C580Y mutationAntimicrobial agents and chemotherapy · 2025Article
- Artemisinin-resistant malaria.Clinical microbiology reviews · 2024Review
- Enhanced cell stress response and protein degradation capacity underlie artemisinin resistance inmSphere · 2024Article
- Artemisinin-resistant Plasmodium falciparum Kelch13 mutant proteins display reduced heme-binding affinity and decreased artemisinin activation.Communications biology · 2024Article
- Emergence, transmission dynamics and mechanisms of artemisinin partial resistance in malaria parasites in Africa.Nature reviews. Microbiology · 2024Review
- Article
- Chemo-proteomics in antimalarial target identification and engagement.Medicinal research reviews · 2023Review
- The role ofProceedings of the National Academy of Sciences of the United States of America · 2023Article
- Chemogenomic Profiling of a Plasmodium falciparum Transposon Mutant Library Reveals Shared Effects of Dihydroartemisinin and Bortezomib on Lipid Metabolism and Exported Proteins.Microbiology spectrum · 2023Article
- Parasite proteostasis and artemisinin resistance.Research square · 2023Article
4 more citing papers are in PubMed but not listed here.
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
12 authors at 3 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Current first-line artemisinin antimalarials are threatened by the emergence of resistant Plasmodium falciparum. Decreased sensitivity is evident in the initial (early ring) stage of intraerythrocytic development, meaning that it is crucial to understand the action of artemisinins at this stage. Here, we examined the roles of iron (Fe) ions and haem in artemisinin activation in early rings using Fe ion chelators and a specific haemoglobinase inhibitor (E64d). Quantitative modelling of the antagonism accounted for its complex dependence on the chemical features of the artemisinins and on the drug exposure time, and showed that almost all artemisinin activity in early rings (>80%) is due to haem-mediated activation. The surprising implication that haemoglobin uptake and digestion is active in early rings is supported by identification of active haemoglobinases (falcipains) at this stage. Genetic down-modulation of the expression of the two main cysteine protease haemoglobinases, falcipains 2 and 3, renders early ring stage parasites resistant to artemisinins. This confirms the important role of haemoglobin-degrading falcipains in artemisinin activation, and shows that changes in the rate of artemisinin activation could mediate high-level artemisinin resistance.
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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.