ArticleProceedings of the National Academy of Sciences of the United States of America2015
Mechanisms of hematin crystallization and inhibition by the antimalarial drug chloroquine.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 62 papers.
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Who cites it
62 citing papers in PubMed, 195 citations in OpenAlex.
- Navigating Classical and Nonclassical Realms of Nucleation and Crystallization.Small (Weinheim an der Bergstrasse, Germany) · 2026Review
- Evaluation of Antiplasmodial Activity of Quinoline Derivatives Incorporating Arylnitro and Aminochalcone Moieties.Pharmaceuticals (Basel, Switzerland) · 2026Article
- Article
- 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
- Lattice bond chains administer kink anisotropy and inform strategies of theophylline crystal self-healing.iScience · 2025Article
- The plasmepsin-piperaquine paradox persists in Plasmodium falciparum.PLoS pathogens · 2025Article
- Bio-inspired multifunctional disruptors of calcium oxalate crystallization.Nature communications · 2025Article
- Nanotechnology meets medicine: applications of atomic force microscopy in disease.Biophysical reviews · 2025Review
- Molecular basis of the functional conflict between chloroquine and peptide transport in the Malaria parasite chloroquine resistance transporter PfCRT.Nature communications · 2025Article
- Direct observation of cholesterol monohydrate crystallization.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Stereospecific Resistance to N2-Acyl Tetrahydro-β-carboline Antimalarials Is Mediated by a PfMDR1 Mutation That Confers Collateral Drug Sensitivity.ACS infectious diseases · 2025Article
- Targeting Malaria's Achilles' Heels: A Review of Plasmodium Life Cycle Vulnerabilities for Drug Discovery.Current topics in medicinal chemistry · 2025Review
- Innate immune and endoplasmic reticulum unfolded protein response pathways protectJournal of biosciences · 2025Article
- A dual growth mode unique for organic crystals relies on mesoscopic liquid precursors.Communications chemistry · 2024Article
- Cryo-tomography and 3D Electron Diffraction Reveal the Polar Habit and Chiral Structure of the Malaria Pigment Crystal Hemozoin.ACS central science · 2024Article
- Article
- Tartronic Acid as a Potential Inhibitor of Pathological Calcium Oxalate Crystallization.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2024Article
- Spectrally Resolved and Highly Parallelized Raman Difference Spectroscopy for the Analysis of Drug-Target Interactions between the Antimalarial Drug Chloroquine and Hematin.Analytical chemistry · 2024Article
- The Digestive Vacuole of the Malaria Parasite: A Specialized Lysosome.Pathogens (Basel, Switzerland) · 2024Review
2 more citing papers are in PubMed but not listed here.
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Authors and funding
4 authors at 1 institution in 1 country.
Funding
Abstract
Hematin crystallization is the primary mechanism of heme detoxification in malaria parasites and the target of the quinoline class of antimalarials. Despite numerous studies of malaria pathophysiology, fundamental questions regarding hematin growth and inhibition remain. Among them are the identity of the crystallization medium in vivo, aqueous or organic; the mechanism of crystallization, classical or nonclassical; and whether quinoline antimalarials inhibit crystallization by sequestering hematin in the solution, or by blocking surface sites crucial for growth. Here we use time-resolved in situ atomic force microscopy (AFM) and show that the lipid subphase in the parasite may be a preferred growth medium. We provide, to our knowledge, the first evidence of the molecular mechanisms of hematin crystallization and inhibition by chloroquine, a common quinoline antimalarial drug. AFM observations demonstrate that crystallization strictly follows a classical mechanism wherein new crystal layers are generated by 2D nucleation and grow by the attachment of solute molecules. We identify four classes of surface sites available for binding of potential drugs and propose respective mechanisms of drug action. Further studies reveal that chloroquine inhibits hematin crystallization by binding to molecularly flat {100} surfaces. A 2-μM concentration of chloroquine fully arrests layer generation and step advancement, which is ∼10(4)× less than hematin's physiological concentration. Our results suggest that adsorption at specific growth sites may be a general mode of hemozoin growth inhibition for the quinoline antimalarials. Because the atomic structures of the identified sites are known, this insight could advance the future design and/or optimization of new antimalarials.
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