title: Differential Binding of Rimantadine Enantiomers to Influenza A M2 Proton Channel.
abstract: 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 (13)C-(2)H 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.
authors.affiliation: National High Magnetic Field Laboratory, Florida State University , Tallahassee, Florida 32310, United States.
authors.forename: Anna K
authors.initials: AK
authors.lastname: Wright
authors.forename: Paratchata
authors.initials: P
authors.lastname: Batsomboon
authors.forename: Jian
authors.initials: J
authors.lastname: Dai
authors.affiliation: National High Magnetic Field Laboratory, Florida State University , Tallahassee, Florida 32310, United States.
authors.forename: Ivan
authors.initials: I
authors.lastname: Hung
authors.forename: Huan-Xiang
authors.initials: HX
authors.lastname: Zhou
authors.forename: Gregory B
authors.initials: GB
authors.lastname: Dudley
authors.affiliation: National High Magnetic Field Laboratory, Florida State University , Tallahassee, Florida 32310, United States.
authors.forename: Timothy A
authors.initials: TA
authors.lastname: Cross
mesh_terms: D000998:Antiviral Agents / Q000737:chemistry / Q000378:metabolism*; D006860:Hydrogen Bonding; D009682:Magnetic Resonance Spectroscopy; D011485:Protein Binding; D012299:Rimantadine / Q000737:chemistry / Q000378:metabolism*; D013237:Stereoisomerism; D014763:Viral Matrix Proteins / Q000378:metabolism*; D000086082:Viroporin Proteins
chemical_list: D000998:Antiviral Agents; D012299:Rimantadine; D014763:Viral Matrix Proteins; C488937:M2 protein, Influenza A virus; D000086082:Viroporin Proteins