2. Academic Validation
  3. Binding and Proton Blockage by Amantadine Variants of the Influenza M2WT and M2S31N Explained

Binding and Proton Blockage by Amantadine Variants of the Influenza M2WT and M2S31N Explained

  • J Med Chem. 2017 Mar 9;60(5):1716-1733. doi: 10.1021/acs.jmedchem.6b01115.
Christina Tzitzoglaki 1,  Anna Wright 2,  Kathrin Freudenberger 3,  Anja Hoffmann 4,  Ian Tietjen 5,  Ioannis Stylianakis 1,  Felix Kolarov 3,  David Fedida 5,  Michaela Schmidtke 4,  Günter Gauglitz 3,  Timothy A Cross 2 6,  Antonios Kolocouris 1
Affiliations

Affiliations

  • 1 Section of Pharmaceutical Chemistry, Department of Pharmacy, National and Kapodistrian University of Athens , Athens 157 71, Greece.
  • 2 Institute of Molecular Biophysics and National High Magnetic Field Laboratory, Florida State University , Tallahassee, Florida 32306, United States.
  • 3 Institut für Physikalische und Theoretische Chemie, Eberhard-Karls Universität , Auf der Morgenstelle 18, D-72076 Tübingen, Germany.
  • 4 Department of Virology and Antiviral Therapy, Jena University Hospital , Hans Knoell Strasse 2, D-07745 Jena, Germany.
  • 5 Department of Anesthesiology, Pharmacology and Therapeutics, University of British Columbia , Vancouver, British Columbia V6T 1Z3, Canada.
  • 6 Department of Chemistry and Biochemistry, Florida State University , Tallahassee, Florida 32306, United States.
PMID: 28107633 DOI: 10.1021/acs.jmedchem.6b01115
Abstract

While aminoadamantanes are well-established inhibitors of the influenza A M2 proton channel, the mechanisms by which they are rendered ineffective against M2S31N are unclear. Solid state NMR, isothermal titration calorimetry, electrophysiology, Antiviral assays, and molecular dynamics simulations suggest stronger binding interactions for aminoadamantanes to M2WT compared to negligible or weak binding to M2S31N. This is due to reshaping of the M2 pore when N31 is present, which, in contrast to wild-type (WT), leads (A) to the loss of the V27 pocket for the adamantyl cage and to a predominant orientation of the ligand's ammonium group toward the N-terminus and (B) to the lack of a helical kink upon ligand binding. The kink, which reduces the tilt of the C-terminal helical domain relative to the bilayer normal, includes the W41 primary gate for proton conductance and may prevent the gate from opening, representing an alternative view for how these drugs prevent proton conductance.

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