Differential Binding of Rimantadine Enantiomers to Influenza A M2 Proton Channel

• Published in: Journal of the American Chemical Society 2016-02, Vol.138 (5), p.1506-1509
• Main Authors: Wright, Anna K, Batsomboon, Paratchata, Dai, Jian, Hung, Ivan, Zhou, Huan-Xiang, Dudley, Gregory B, Cross, Timothy A
• Format: Article
• Language: English
• Subjects: Antiviral Agents - chemistry; Antiviral Agents - metabolism; Hydrogen Bonding; Magnetic Resonance Spectroscopy; Protein Binding; Rimantadine - chemistry; Rimantadine - metabolism; Stereoisomerism; Viral Matrix Proteins - metabolism
• ISSN: 0002-7863; 1520-5126
• DOI: 10.1021/jacs.5b13129

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.