Differential Binding of Rimantadine Enantiomers to Influenza A M2 Proton Channel

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• 作者：Anna K. Wright ; Paratchata Batsomboon ; Jian Dai ; Ivan Hung ; Huan-Xiang Zhou ; Gregory B. Dudley ; Timothy A. Cross
• 刊名：Journal of the American Chemical Society
• 出版年：2016
• 出版时间：February 10, 2016
• 年：2016
• 卷：138
• 期：5
• 页码：1506-1509
• 全文大小：303K
• ISSN：1520-5126

文摘

Rimantadine hydrochloride (α-methyl-1-adamantane-methalamine hydrochloride) is a chiral compound which exerts antiviral activity against the influenza A virus by inhibiting proton conductance of the M2 ion channel. In complex with M2, rimantadine has always been characterized as a racemic mixture. Here, we report the novel enantioselective synthesis of deuterium-labeled (R)- and (S)-rimantadine and the characterization of their protein–ligand interactions using solid-state NMR. Isotropic chemical shift changes strongly support differential binding of the enantiomers to the proton channel. Position restrained simulations satisfying distance restraints from ¹³C–²H rotational-echo double-resonance NMR show marked differences in the hydrogen-bonding pattern of the two enantiomers at the binding site. Together these results suggest a complex set of interactions between (R)-rimantadine and the M2 proton channel, leading to a higher stability for this enantiomer of the drug in the channel pore.