The new aminoadamantane nitrates can inhibit SARS-CoV-2 infection

Researchers from Scripps Research Institute – California-USA have created a variant of the generic drug Memantine which is an Aminoadamantane compound, to inhibit the SARS-CoV-2 virus entry by targeting the ACE2 receptors.

The study findings were published in the peer reviewed journal: Nature Chemical Biology. 

https://www.nature.com/articles/s41589-022-01149-6

In summary, development of an oral drug to combat acute SARS-Cov-2 infection remains a high priority to treat the COVID-19 pandemic, particularly for the unvaccinated segment of the world population. Our findings provide proof of concept that the cellular receptor of SARS-CoV-2, ACE2, can be S-nitrosylated.

This nitrosylation reaction appears to inhibit binding of SARS-CoV-2 spike protein, thus inhibiting viral entry, infectivity and cytotoxicity. As emerging evidence for this mechanism of action, our binding, co-IP and Cys mutation experiments show a significant degree of disruption of binding of spike protein to ACE2 after S-nitrosylation of ACE2 or after mutation of the S-nitrosylation sites on ACE2.

In fact, this mechanism was predicted in our molecular dynamics (MD) simulation experiments. We acknowledge, however, that, although this is a rational explanation, it remains a hypothesis for the observed mechanism of viral inhibition by chemical probes that S-nitrosylate ACE2.

Taking advantage of these findings, we developed a novel aminoadamantane nitrate compound, NMT5, as a chemical probe that provides inhibition of SARS-CoV-2 activity by protein S-nitrosylation. NMT5 contains a nitro group, and we provide evidence that this nitro group is targeted to ACE2 by aminoadamantane-mediated viroporin channel blockade of the E protein2,3,10,11,12.

The discovery that ACE2 could be S-nitrosylated was quite unexpected, as most authorities had postulated that the beneficial effects of NO on patients with COVID-19 was due to a direct effect on the virus itself. These mechanistic insights provided by our chemical probes should facilitate development of aminoadamantane nitrate drugs for acute antiviral therapy for human COVID-19.

A key concept of this novel approach to ameliorating infection by SARS-CoV-2 is that these nitro-aminoadamantane compounds may prevent the viral spike protein from binding to the ACE2 receptor by S-nitrosylating the receptor in targeted fashion, apparently facilitated by blockade of the vicinal viroporin E protein (Fig. 5 and Extended Data Figs. 9 and 10).

Hence, drugs like NMT5 should also prevent new variants of the spike protein from binding to ACE2 because ACE2 itself is blocked. In this manner, the development of aminoadamantane nitrates for COVID-19 drug therapy complements other drug, vaccine and antibody therapies, which are dependent on spike protein antigenic sites and, thus, may eventually be susceptible to evasion by further spike protein mutation.

Critically, the binding of NMT5 to the viroporin channel may also confer the ability to block spread of SARS-CoV-2 from one host to another. To explain this mechanistically, we posit that NMT5 binds to the E protein viroporin channel on SARS-CoV-2 and then transfers NO to ACE2 on the host cell to prevent infection (Fig. 5a,b and Extended Data Fig. 9).

However, if a patient is already infected and takes an NMT5-like drug, the newly produced viral particles will bind to the aminoadamantane moiety of NMT5 via their E protein viroporin channels; hence, viral infectivity should be limited when a new potential host is exposed to this virus because the new host’s ACE2 target protein will be S-nitrosylated by the drug attached to the viral particles as the virus approaches ACE2 on the new host.

Compounds like NMT5 thus provide tools for the development of a novel strategy to combat spread of COVID-19 from one host to another.