Dynamic Interactions of the S-Nitrosoproteome in Type 2 Diabetes/Metabolic Syndrome and Alzheimer's Disease

COVID-19-Related Administrative Supplement to NIA RF1 AG057409 under PA-18-591 and NOT-AG-20-022Project Summary: Epidemiological studies of pandemic COVID-19 suggest that aged populations, especially those withAlzheimer's disease and related dementias (AD)/ADRD, are particularly vulnerable. We therefore propose anAdministrative Supplement for work in line with the Division of Neuroscience at NIA, namely, "studies aimed atdiscovery and development of novel drugs, as well as repurposing and repositioning existing drugs, forpreventing and treating COVID-19, particularly drugs that are specific for COVID-19 related CNS targets andCNS mechanisms related to or driving the viral-mediated pathophysiology." Specifically, we will test drugsdeveloped in the parent RF1 award by screening them for anti-viral activity to fight the infection andtreat potential CNS ramifications in AD/ADRD and aged populations. Intriguingly, aminoadamantanedrugs (e.g., amantadine, rimantadine, and memantine) were first discovered as anti-viral agents because theycan block the ion channel found in the envelope of viruses such as influenza, but also found in the SARS-CoVfamily. The PI, Dr. Lipton, subsequently found that these aminoadamantanes had activity in the CNS byblocking excessively-activated NMDAR-associated ion channels, and Lipton's work eventually led to FDAapproval of memantine for use in AD. Recently, the Lipton group designed and synthesized aminoadamantanenitrate drugs under the auspices of the parent RF1 Award to be used to inhibit excessively-activated NMDARsto a much higher degree than memantine by adding a nitro-based warhead to an aminoadamantane in order toS-nitrosylate (via covalent reaction of NO) and thus further inhibit receptor activity in a targeted fashion. As aseemingly amazing coincidence, it was recently reported that the SARS-CoV family of viruses are susceptibleto NO, in part by inhibiting their replication cycle. However, the delivery of NO or a NO-related species to analready ill patient could have severe consequences, such as lowering the blood pressure dramatically. Hence,in this proposal we develop a novel targeted delivery of NO-related species directly to the SARS-CoV-2 virusby using the aminoadamantane moiety that binds to the envelope ion channel and has a nitro-based warheadthat it then delivers directly to the virus. Another critical feature of the current proposal is that we use thesesame aminoadamantane nitrate compounds to protect the brain from injury potentially engendered by the virusvia inhibition of excessive NMDAR activity. Importantly, up to 37% of patients hospitalized for severe COVID-19 reportedly display neurological sequelae. Mechanistically in this regard, in the face of severe viral infections,including coronaviruses, excessive levels of glutamate are released (or not taken up) by astrocytes, leading toglutamate-related neurotoxicity (excitotoxicity). In our parent RF1 grant, we reported similar findings in AD, i.e.,that Aß-stimulated astrocytes release glutamate onto neurons. Therefore, this Administrative Supplement willtest the top 'hits' of aminoadamantane nitrates capable of inhibiting SARS-CoV-2 in additional screens for theirability to prevent viral-related damage to neurons in the brains of AD/ADRD and aged populations.