Document text
Principal Investigator: STUART A LIPTON
Organization: SCRIPPS RESEARCH INSTITUTE, THE
Fiscal Year: 2020
Award: $177,500
Funding agency: National Institute on Drug Abuse
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.
Terms: <2019 novel coronavirus><2019-nCoV><AD dementia><AIDS Virus><Acquired Immune Deficiency Syndrome Virus><Acquired Immunodeficiency Syndrome Virus><Address><Administrative Supplement><Affect><Alzheimer><Alzheimer Type Dementia><Alzheimer disease><Alzheimer sclerosis><Alzheimer syndrome><Alzheimer's><Alzheimer's Disease><Alzheimer's disease dementia><Alzheimers Dementia><Alzheimers disease><Antiviral Agents><Antiviral Drugs><Antivirals><Award><Brain><Brain Nervous System><COVID-19><COVID-19 epidemic><COVID-19 pandemic><COVID19><COVID19 epidemic><COVID19 pandemic><California><Communities><Core Facility><Crystal Meth><Deoxyephedrine><Desoxyephedrine><Development><Drug usage><Drugs><Encephalon><Endogenous Nitrate Vasodilator><Endothelium-Derived Nitric Oxide><Family><Grant><HIV><HIV 1 associated neurocognitive disorder><HIV-1 associated neurocognitive disorder><HIV-associated neurocognitive disorder><Human Immunodeficiency Viruses><Infection><Ion Channel><Ionic Channels><LAV-HTLV-III><Lead><Lung diseases><Lymphadenopathy-Associated Virus><METH use><METH using><Medication><Membrane Channels><Methamphetamine><Methylamphetamine><Mononitrogen Monoxide><N-Methylamphetamine><NIDA><NO3-><Names><National Institute of Drug Abuse><National Institute on Drug Abuse><Nerve Cells><Nerve Unit><Nervous System Diseases><Neural Cell><Neurocyte><Neurologic Disorders><Neurological Disorders><Neurons><Nitrates><Nitric Oxide><Nitrogen Monoxide><Nitrogen Protoxide><Parents><Patients><Pb element><Pharmaceutic Preparations><Pharmaceutical Preparations><Population><Post-Translational Modification Protein/Amino Acid Biochemistry><Post-Translational Modifications><Post-Translational Protein Modification><Post-Translational Protein Processing><Posttranslational Modifications><Posttranslational Protein Processing><Primary Senile Degenerative Dementia><Protein Modification><Pulmonary Diseases><Pulmonary Disorder><Reporting><Research><Research Institute><Respiratory Disease><Respiratory System Disease><Respiratory System Disorder><SARS-CoV-2><SARS-CoV2><SARS-associated coronavirus 2><SARS-coronavirus-2><SARS-related coronavirus 2><Series><Severe acute respiratory syndrome coronavirus 2><Substance Use Disorder><Testing><Therapeutic><Therapeutic Agents><Viral><Viral Activity><Viral Function><Viral Physiology><Virus><Virus-HIV><Work><Wuhan coronavirus><anti-viral agents><anti-viral drugs><anti-virals><co-morbid><co-morbidity><comorbidity><corona virus disease 2019><corona virus disease 2019 epidemic><corona virus disease 2019 pandemic><coronavirus disease 2019><coronavirus disease 2019 epidemic><coronavirus disease 2019 pandemic><dementia of the Alzheimer type><developmental><disease of the lung><disorder of the lung><drug development><drug use><drug/agent><endothelial cell derived relaxing factor><fighting><heavy metal Pb><heavy metal lead><lung disorder><meth abuse><methamphetamine abuse><methamphetamine use><methamphetamine using><nervous system disorder><neurological disease><neuronal><new approaches><novel><novel approaches><novel strategies><novel strategy><pandemic><pandemic disease><primary degenerative dementia><senile dementia of the Alzheimer type><side effect><site targeted delivery><targeted delivery><virus envelope>