Monday, November 25, 2024
11/25/2024
COVID-19-Related Administrative Supplement to DP1 DA041722 under PA-18-591 and NOT-DA-20-047 PROJECT SUMMARY The worldwide pandemic of the 2019 novel coronavirus, or COVID-19, has led the research community to believe the possibility that it could affect some populations with substance use disorders or HIV particularly hard. Therefore, we propose new work here that is “in scope” with our parent NIDA DP1 grant (DP1 DA041722) that would potentially address the pandemic, at least in part, by developing an anti-viral drug to fight the infection. We propose, as listed in NOT-DA-20-047, to perform “research to develop therapeutic approaches 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 patients with HIV-associated neurocognitive disorder (HAND) and drug use, particularly methamphetamine. During the course of these studies, we developed a novel series of therapeutic agents in the class of compounds called aminoadamantane nitrates, with the lead drug designated NitroSynapsin, that have shown activity in protecting neurons in the context of HIV/methamphetamine abuse as well as in the context of Alzheimer’s disease and other neurologic disorder. Our novel approach concerns the fact that this family of agents that we developed may also show activity at the ion channel in the envelope of the SARS-CoV-2 virus, the causative agent of the COVID-19 pandemic. The mechanism of action (MOA) that we propose against SARS-CoV-2 is best summarized 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 related compounds have been reported to inhibit this class of viruses. We reasoned in a novel fashion that the targeted delivery of NO-related species to the virus would avoid systemic side effects of NO-like drugs. For this purpose (but originally for use in the brain), we had devised a series of aminoadamantane nitrates, with the aminoadamantane 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 test our drugs in an ongoing screen against SARS-CoV-2 viral activity in our Calibr Drug Development Core Facility at The Scripps Research Institute in La Jolla, California.
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