文章基本信息

标题：Antimalarials inhibit hematin crystallization by unique drug–surface site interactions
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作者：Katy N. Olafson ; Tam Q. Nguyen ; Jeffrey D. Rimer 等
期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2017
卷号：114
期号：29
页码：7531-7536
DOI：10.1073/pnas.1700125114
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：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 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.
关键词：malaria ; P. falciparum ; crystallization inhibition ; hematin crystals ; heme detoxification