ArticleThe Journal of biological chemistry
A second mechanism employed by artemisinins to suppress Plasmodium falciparum hinges on inhibition of hematin crystallization.
Article in The Journal of biological chemistry. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 25 papers.
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Who cites it
25 citing papers in PubMed, 51 citations in OpenAlex.
- Why are iron chelators not as effective as artemisinin in killing malaria parasites?Parasites & vectors · 2026Article
- Inhibitors of cytochromemBio · 2026Article
- A Fe-incorporated bioreactor platform exhibiting antimalarial activity and enhanced response to artemisinin.Antimicrobial agents and chemotherapy · 2026Article
- Polypharmacology in malaria treatment: single drugs, multiple mechanisms, greater impact.Trends in parasitology · 2026Review
- Heme as activator and target for artemisinin: Towards multiple pharmacological bioactivity.Biochemistry and biophysics reports · 2026Review
- Reversion of heme-dependent metronidazole resistance inMicrobiology spectrum · 2026Article
- A nonclassical pathway of β-hematin crystal nucleation enables its suppression by antimalarials.Communications chemistry · 2025Article
- Tafenoquine Disrupts Intraerythrocytic Stages of Malaria Parasites by Inhibiting Nonclassical Pathways of β-Hematin Nucleation and Growth.Biochemistry · 2025Article
- Pharmacokinetics and metabolism of artemisinin (ART) in Plasmodium yoelii: ART-heme adduct as a potential biomarker for its resistance.International journal for parasitology. Drugs and drug resistance · 2025Article
- Bio-inspired multifunctional disruptors of calcium oxalate crystallization.Nature communications · 2025Article
- ER Stress Induced by Artemisinin and Its Derivatives Determines the Susceptibility to Their Synergistic Apoptotic Killing With TRAIL.Cancer medicine · 2025Article
- Probing Bacterial Interactions with theToxins · 2025Article
- Nanotechnology meets medicine: applications of atomic force microscopy in disease.Biophysical reviews · 2025Review
- Hemozoin: a waste product after heme detoxification?Parasites & vectors · 2025Article
- Uncovering the Mechanism of Action of Antiprotozoal Agents: A Survey on Photoaffinity Labeling Strategy.Pharmaceuticals (Basel, Switzerland) · 2024Review
- Artemisinin-resistant Plasmodium falciparum Kelch13 mutant proteins display reduced heme-binding affinity and decreased artemisinin activation.Communications biology · 2024Article
- Characterization of antimalarial activity of artemisinin-based hybrid drugs.Antimicrobial agents and chemotherapy · 2024Article
- Molecular mechanisms of mitochondria-mediated ferroptosis: a potential target for antimalarial interventions.Frontiers in cell and developmental biology · 2024Review
- Nonclassical mechanisms to irreversibly suppress β-hematin crystal growth.Communications biology · 2023Article
- The role ofProceedings of the National Academy of Sciences of the United States of America · 2023Article
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Authors and funding
8 authors at 2 institutions in 1 country.
Funding
Abstract
Malaria is a pervasive disease that affects millions of lives each year in equatorial regions of the world. During the erythrocytic phase of the parasite life cycle, Plasmodium falciparum invades red blood cells, where it catabolizes hemoglobin and sequesters the released toxic heme as innocuous hemozoin crystals. Artemisinin (ART)-class drugs are activated in vivo by newly released heme, which creates a carbon-centered radical that markedly reduces parasite density. Radical damage to parasite lipids and proteins is perceived to be ARTs' dominant mechanism of action. By contrast, quinoline-class antimalarials inhibit the formation of hemozoin and in this way suppress heme detoxification. Here, we combine malaria parasite assays and scanning probe microscopy of growing β-hematin crystals to elucidate an unexpected mechanism employed by two widely administered antimalarials, ART, and artesunate to subdue the erythrocytic phase of the parasite life cycle. We demonstrate that heme-drug adducts, produced after the radical activation of ARTs and largely believed to be benign bystanders, potently kills P. falciparum at low exogenous concentrations. We show that these adducts inhibit β-hematin crystallization and heme detoxification, a pathway which complements the deleterious effect of radicals generated via parent drug activation. Our findings reveal an irreversible mechanism of heme-ART adduct inhibition of heme crystallization, unique among antimalarials and common crystal growth inhibitors, that opens new avenues for evaluating drug dosing regimens and understanding growing resistance of P. falciparum to ART.
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