Repurposing of Adamantanes with Transmitter Receptor Antagonist Properties for the Prevention/Treatment of COVID-19

Abstract

Members of the adamantane family of agents in general and two such members, amantadine and memantine, in particular, have established beneficial actions across a wide range of infectious diseases including those caused by coronaviruses. Increasing evidence suggests that the protective effects of these agents is the result of actions on neurotransmitter systems namely the NMDA receptor subclass of the glutamatergic system and by the α7-nACh subclass of nicotinic cholinergic receptor. The potent NMDA receptor antagonist, memantine, prevents motor disabilities and reduces replication of the neuroinvasive/neurotropic human respiratory virus HCoV-OC43 dose-dependently. Moreover, the lysosomotrophic adamantanes amantadine and memantine also limit viral replication. Known lysomotrophic agents such as ammonium chloride inhibit cellular entry of SARS-CoV-2 on laboratory testing. Inhibiting clathrinmediated endocytosis (cellular entry) of the SARS-CoV-2/ACE2 complex by amantadine or rimantadine may block viral entry into vulnerable cellular populations, and also reduce platelet activating factor-priming of Polymorphonuclear [PMN] cells, potentially lessening PMN cell-mediated tissue damage and excess Neutrophil Extracellular Traps [NETs] seen in advanced cases of COVID-19. Rimantadine has inhibitory effects of SARS-CoV-1, a closely-related virus to SARS-CoV-2, which may indicate the need for further evaluation as a treatment for COVID-19. Amantadine increases Dopamine [DA] release and blocks its reuptake, increasing its action on DA receptors on T cells thus activating resting effector T cells and suppressing regulator T cells, which may have a beneficial immunomodulating function in infectious diseases. Proposed adverse effects of smoking on COVID-19 outcomes are attributed to the effects of nicotine via the α7-nACh receptor located on bronchial and alveolar epithelial cells. As an antagonist of this receptor, memantine has the potential to prevent the entry of SARS-CoV-2 into these cells. Independent case reports provide evidence of protective effects of amantadine and/or memantine against COVID-19. Additional epidemiologic studies however indicate a lower incidence of smoking in hospitalized patients, stimulating investigations of nicotine-related aspects, and amino acid sequence analysis indicate homologous sequences with those of neurotoxins seen in snake venoms blocking the α7-nAChR suggesting that COVID-19 may be a disease of the nicotinic cholinergic system; α7-nAChR is involved in the cholinergic anti-inflammatory pathway or reflex. COVID-19 is a biphasic disease, the initial aspect involved with the initial infection and viral replication which stimulates a prominent innate immune response. This then transitions to the adaptive immune response with suppression of infection and recovery, while the innate response is suppressed via the cholinergic anti-inflammatory pathway. Severe disease may occur when the initial innate immune response continues, the cholinergic anti-inflammatory pathway being arrested by the neu...

Efficacy of Ion-Channel Inhibitors Amantadine, Memantine and Rimantadine for the Treatment of SARS-CoV-2 In Vitro

“…Future studies should investigate the mechanism of action and SARS-CoV-2 targets of the tested inhibitors. In vitro studies suggested amantadine to target SARS-CoV-2 protein E, which was suggested to have ion-channel function [ 6 , 25 ]. Further, amantadine was shown to inhibit the expression of a lysosomal gene involved in the viral entry of SARS-CoV-2 in vitro [ 26 ].…”

Potential for the Repurposing of Adamantane Antivirals for COVID-19

“…Binding of the SARS-CoV-2 spike to ACE2 is followed by action of the endosomal cysteine protease Cathepsin L [CTSL], resulting in fusion of viral and host cell membranes and release of the viral genome into the host cell cytoplasm. Amantadine has the potential to disrupt the process by down-regulation of CTSL by increasing the pH of endosomes, resulting in impaired viral entry and replication [ 20 ] …”

“…Damage to the central nervous system (CNS) is well established in COVID-19 and it has been suggested that the neuroinvasive nature of SARS-CoV-2 may contribute to the acute respiratory failure characteristic of COVID-19 [ 19 ]. There is evidence to suggest that amantadine and memantine exert their protective effects against COVID-19 via mechanisms involving specific CNS neurotransmitter systems [ 20 ]. Both amantadine and memantine are potent antagonists of the NMDA subclass of glutamate receptor and memantine prevents motor incoordination problems in animals infected with the neuroinvasive HCoV-OC43 with concomitant suppression of viral replication in a dose-dependent manner.…”

“…The proposal that certain adamantanes (amantadine, memantine) may be of benefit for the treatment of neurological complications of COVID-19 by virtue of their established actions as mediators of key excitatory and inhibitory neurotransmitter systems [ 20 ] will likely lead to continued work in this area that could result in novel therapies for the characteristic CNS symptoms of “long COVID-19”.…”

Possibilities of using amantadines in the setting of the novel coronavirus infection in patients with Parkinson's disease

“…Вовлечение стволовых структур может способствовать развитию острой дыхательной недостаточности, характерной для COVID-19 [20][21][22]. Амантадин и мемантин не только реализуют свой защитный потенциал в отношении центральной нервной системы, блокируя нейроинвазию, но и обладают нейропротекторным эффектом, влияя на механизмы эксайтотоксичности, оксидативного стресса, нейровоспаления за счет блокады NMDA-рецепторов [23][24][25] (рис. 2).…”