Τίτλος:
Binding and Proton Blockage by Amantadine Variants of the Influenza M2WT and M2S31N Explained
Γλώσσες Τεκμηρίου:
Αγγλικά
Περίληψη:
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. © 2017 American Chemical Society.
Συγγραφείς:
Tzitzoglaki, C.
Wright, A.
Freudenberger, K.
Hoffmann, A.
Tietjen, I.
Stylianakis, I.
Kolarov, F.
Fedida, D.
Schmidtke, M.
Gauglitz, G.
Cross, T.A.
Kolocouris, A.
Περιοδικό:
Journal of Medicinal Chemistry
Εκδότης:
American Chemical Society
Λέξεις-κλειδιά:
amantadine derivative; amantadine; antivirus agent; ligand; M2 protein, Influenza A virus; matrix protein; proton, amino terminal sequence; animal cell; Article; binding affinity; carboxy terminal sequence; controlled study; drug binding site; drug potency; drug structure; drug synthesis; electrophysiology; hydrogen bond; IC50; in vitro study; Influenza A virus; isothermal titration calorimetry; ligand binding; lipid bilayer; MDCK cell line; molecular dynamics; molecular recognition; nitrogen nuclear magnetic resonance; nonhuman; peptide synthesis; pH; protein structure; proton nuclear magnetic resonance; proton transport; reduction (chemistry); reversed phase high performance liquid chromatography; solid state; surface plasmon resonance; thermodynamics; virus replication; virus strain; antagonists and inhibitors; drug effects; Influenza A virus; metabolism; spectroscopy, Amantadine; Antiviral Agents; Influenza A virus; Ligands; Protons; Spectrum Analysis; Viral Matrix Proteins
DOI:
10.1021/acs.jmedchem.6b01115
