Repurposing of Adamantanes for the Treatment of COVID-19: Rationale and Perspectives

Abstract

Intensive efforts are underway in the search for novel antiviral agents and in the repurposing of existing antivirals with the potential to mitigate the effects of COVID-19. Amantadines represent a large family of tricyclic agents some of which are known to manifest efficacy against a range of viruses including influenza A and several human and animal coronaviruses including SARS-CoV and HCoV-OC43 with neuroinvasive characteristics. The adamantane derivative memantine improves clinical scores and motor disabilities while reducing HCoV-OC43 viral replication in a dose-dependent manner. Anti-viral actions of memantine against HCoV are independent of the agent's action as a non-competitive NMDA receptor antagonist. Amantadine and the novel spiroadamantane amine possess significant activity against coronavirus 229E. Mechanisms proposed to date to account for the anti-SARS CoV-2 actions of adamantanes include blocking of the viroporin channel of the virus E protein preventing release of viral nucleus into the host-cell cytoplasm and down-regulation of the host protease CTSL and lysosomal disruption leading to decreased viral replication. Further investigations are now required including the assessment of other adamantanes as antivirals in the experimental setting and controlled clinical trials to assess their safety and efficacy for the prevention and treatment of COVID-19.