Department of Chemical and Biomolecular Engineering, University of Houston, Houston, TX 77204-4004.
Department of Chemical and Biomolecular Engineering, University of Houston, Houston, TX 77204-4004;
Proc Natl Acad Sci U S A. 2017 Jul 18;114(29):7531-7536. doi: 10.1073/pnas.1700125114. Epub 2017 May 30.
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.
在疟疾病理生理学中，关于血红素结晶抑制的不同假说认为，药物的作用要么是通过隔离可溶性血红素，要么是通过与晶体表面相互作用。我们使用生理相关的、时间分辨的原位表面观察方法，表明喹啉类抗疟药通过三种不同的作用方式抑制β-血红素晶体表面：台阶钉扎、扭结阻塞和台阶束诱导。扭结阻塞的详细实验证据验证了经典理论，并表明该机制不是最有效的抑制途径。喹啉类药物也与可溶性血红素形成各种复合物，但络合不足以抑制血红素解毒，并且是药物特异性的不良指标。总的来说，我们的发现揭示了药物-晶体相互作用的重要性，并为合理设计抗疟化合物开辟了途径。
