Development of a Targeted Nitric Oxide-Related Drug to treat SARS-CoV-2

COVID-19-Related Administrative Supplement to DP1 DA041722 under PA-18-591 and NOT-DA-20-047PROJECT SUMMARYThe worldwide pandemic of the 2019 novel coronavirus, or COVID-19, has led the research community tobelieve the possibility that it could affect some populations with substance use disorders or HIV particularlyhard. Therefore, we propose new work here that is "in scope" with our parent NIDA DP1 grant (DP1DA041722) that would potentially address the pandemic, at least in part, by developing an anti-viral drug tofight the infection. We propose, as listed in NOT-DA-20-047, to perform "research to develop therapeuticapproaches for comorbid SARS-CoV-2 infection." In the parent DP1 grant, we are studying the nitric oxide(NO)-related posttranslational modification of proteins, which we previously named S-nitrosylation, in patientswith HIV-associated neurocognitive disorder (HAND) and drug use, particularly methamphetamine. During thecourse of these studies, we developed a novel series of therapeutic agents in the class of compounds calledaminoadamantane nitrates, with the lead drug designated NitroSynapsin, that have shown activity in protectingneurons in the context of HIV/methamphetamine abuse as well as in the context of Alzheimer's disease andother neurologic disorder. Our novel approach concerns the fact that this family of agents that we developedmay also show activity at the ion channel in the envelope of the SARS-CoV-2 virus, the causative agent of theCOVID-19 pandemic. The mechanism of action (MOA) that we propose against SARS-CoV-2 is bestsummarized as follows:Compounds in the aminoadamantane family are generally known to block ion channels in envelope viruses,including SARS-CoV-2, which causes COVID-19 respiratory disease. Moreover, nitric oxide (NO) and relatedcompounds have been reported to inhibit this class of viruses. We reasoned in a novel fashion that thetargeted delivery of NO-related species to the virus would avoid systemic side effects of NO-like drugs. For thispurpose (but originally for use in the brain), we had devised a series of aminoadamantane nitrates, with theaminoadamantane moiety acting as a "guided missile" to enter the viral envelope channel and then deliver a"warhead" of a nitro group directly to the virus to disrupt viral activity. Accordingly, we propose to rapidly testour drugs in an ongoing screen against SARS-CoV-2 viral activity in our Calibr Drug Development Core Facilityat The Scripps Research Institute in La Jolla, California.