page_title: Amantadine
section_title: Influenza
hierarchical_section_title: Amantadine / Mechanism of action / Influenza
caption_attribution_description: English: The crystal structure of the transmembrane proton channel domain of the influenza A M2 protein, showing tetrameric arrangement of helices with a channel-blocking drug, amantadine, located in the center (red). The amino acid residues involved in proton transduction are shown as sticks. The image is oriented with the N-terminus at the top; the bottom points toward the interior of the virus. Rendered from PDB ID 3C9J, published in: Jessica L. Thomaston, Mercedes Alfonso-Prieto, Rahel A. Woldeyes, James S. Fraser, Michael L. Klein, Giacomo Fiorin, and William F. DeGrado. (2015) High-resolution structures of the M2 channel from influenza A virus reveal dynamic pathways for proton stabilization and transduction. Proc Natl Acad Sci 112(46): 14260–14265. DOI: 10.1073/pnas.1518493112. URL: http://www.pnas.org/content/112/46/14260
context_page_description: Amantadine, sold under the brand name Gocovri among others, is a medication used to treat dyskinesia associated with parkinsonism and influenza caused by type A influenzavirus, though its use for the latter is no longer recommended due to drug resistance. It acts as a nicotinic antagonist and noncompetitive NMDA antagonist. The antiviral mechanism of action is antagonism of the influenzavirus A M2 proton channel, which prevents viral shedding.
context_section_description: The mechanisms for amantadine's antiviral and antiparkinsonian effects are unrelated. Amantadine targets the influenza A M2 ion channel protein.  The M2 protein's function is to allow the intracellular virus to replicate (M2 also functions as a proton channel for hydrogen ions to cross into the vesicle), and exocytose newly formed viral proteins to the extracellular space (viral shedding).  By blocking the M2 channel, the virus is unable to replicate because of impaired replication, protein synthesis, and exocytosis.
  Amantadine and rimantadine function in a mechanistically identical fashion, entering the barrel of the tetrameric M₂ channel and blocking pore function—i.e., proton translocation.
  Resistance to the drug class is a consequence of mutations to the pore-lining residues of the channel, preventing both amantadine and rimantadine from inhibiting the channel in their usual way.
  Influenza B strains possess a structurally distinct M₂ channel with channel-facing side chains that fully obstruct the channel vis-à-vis binding of adamantine-class channel inhibitors, while still allowing proton flow and channel function to occur; this constriction in the channels is responsible for the ineffectiveness of this drug and rimantadine towards all circulating Influenza B strains.
caption: Model of amantadine (red) inhibiting influenza A M2 protein (blue).[29]
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