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Antimalarials inhibit hematin crystallization by unique drug-surface site interactions.

ABSTRACT: 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 ?-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.

SUBMITTER: Olafson KN

PROVIDER: S-EPMC5530657 | biostudies-literature | 2017 Jul

REPOSITORIES: biostudies-literature

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Antimalarials inhibit hematin crystallization by unique drug-surface site interactions.

Olafson Katy N KN Nguyen Tam Q TQ Rimer Jeffrey D JD Vekilov Peter G PG

Proceedings of the National Academy of Sciences of the United States of America 20170530 29

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 β-hematin crystal surfaces by three distinct modes of action: step pinning, kink blocking, and step bunch induction. Detailed experimental evidence of kink blocking validat ...[more]

PMID: 28559329

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