Repurposing Aminoadamantane Nitrate Compounds to Inhibit SARS-CoV-2 Viral Activity and to Protect the Brain from Viral-Related Damage

We screened a series of aminoadamantane nitrate compounds for therapeutic effect against SARS-CoV-2 viral infection. These drugs work by a dual mechanism, (i) S-nitrosylation of the ACE2 receptor for SARS-CoV-2, which prevents spike (S) protein from binding and hence inhibit viral entry; and (ii) aminoadamantane blockade of the viroporin channel formed by the envelope (E) protein, which inhibits viral propagation. We assessed the cytoprotective efficacy of aminoadamantanes and aminoadamantane nitrate compounds in pseudovirus binging assays and against live SARS-CoV-2 viral infectivity in human cells. As positive controls, we used remdesivir, apilimod, and puromycin. As an in vitro indicator of the therapeutic potential of these compounds, we calculated the half-maximal effective concentration (EC₅₀) of each compound. Among the 9 aminoadamantane or aminoadamantane nitrate compounds tested, the best had an EC₅₀ value well within the low micromolar range, which is attainable in human tissues at well-tolerated doses that have been previously tested in two-animal species for toxicity. We plan to next treat an animal model of SARS-CoV-2 (COVID-19) infection with our lead compound and perform chemical modifications to optimize efficacy under the auspices of other funding.