The uncoating inhibitor amantadine was the first drug approved by the FDA to treat Influenza A infections in 1966. The closely related rimantadine was approved only 30 years later, in 1993. These two drugs are derivates of adamantane, an organic compound with a unique cage-shaped carbon structure. They were the only two uncoating inhibitors ever in clinical use. Both are no longer recommended in the treatment or prevention of Influenza A infections due to high levels of resistance. Amantadine and rimantadine may be effective in Parkinson’s disease likely due to NMDA receptor antagonism.
Amantadine and rimantadine interfere with early-stage influenza A replication. After attachment to the host cell via the haemagglutinin viral envelop protein, the influenza virion is endocytosed. Viral envelope and endosomal membranes fuse and hydrogen ions are pumped into the viral core via the transmembrane M2 (matrix 2) protein channel. This acidification sets free the viral genome (ribonucleoproteins) which are trafficked to the host cell’s nucleus. Uncoating inhibitors block the M2 transmembrane proton pump preventing the release of influenza RNA from the virion and thus inhibiting viral replication. Resistance to uncoating inhibitors is mediated by mutations affecting the M2 protein channel, which reduces drug affinity.
Both amantadine and rimantadine are well absorbed from the gastrointestinal tract. Rimantadine has a longer elimination half life than amantadine (25h vs 15h). In contrast to amantadine, rimantadine is extensively metabolised in the liver. Both drugs and their metabolites are eliminated via the urine.
Uncoating inhibitors are generally well-tolerated drugs. Common side effects include gastrointestinal symptoms and CNS effects (i.e., insomnia, fatigue, dizziness, nervousness).