Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 114, Issue 29, Pages 7531-7536Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1700125114
Keywords
malaria; P. falciparum; crystallization inhibition; hematin crystals; heme detoxification
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Funding
- NIH through the Nanobiology Interdisciplinary Graduate Training Program of the Gulf Coast Consortia for Quantitative Biomedical Sciences [T32EB009379, 1R21AI126215-01]
- NASA [NNX14AD68G, NNX14AE79G]
- Welch Foundation [E-1794]
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In malaria pathophysiology, divergent hypotheses on the inhibition of hematin crystallization posit that drugs act either by the sequestration of soluble hematin or their interaction with crystal surfaces. We use physiologically relevant, time-resolved in situ surface observations and show that quinoline antimalarials inhibit beta-hematin crystal surfaces by three distinct modes of action: step pinning, kink blocking, and step bunch induction. Detailed experimental evidence of kink blocking validates classical theory and demonstrates that this mechanism is not the most effective inhibition pathway. Quinolines also form various complexes with soluble hematin, but complexation is insufficient to suppress heme detoxification and is a poor indicator of drug specificity. Collectively, our findings reveal the significance of drug-crystal interactions and open avenues for rationally designing antimalarial compounds.
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