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Principal Investigator: JOHN M. LITTLETON
Organization: NAPROGENIX, INC
Fiscal Year: 2020
Award: $140,059
Funding agency: National Institute on Alcohol Abuse and Alcoholism
Abstract
The parent award is to develop novel medications for alcohol and nicotine use disorders. These
disorders have increased during COVID19 [e.g. Clay and Parker 2020] and are associated with
increased susceptibility to, and severity of, infection. This supplemental proposal is focused on
how mechanisms of COVID-19 infection and neurotoxicity are influenced by alcohol and nicotine,
and how these novel medications interact with these mechanisms. The applicants have previously
used organotypic hippocampal neuronal cultures to study interactions between nicotine, alcohol
withdrawal and viral protein neurotoxicity, and these cultures will be used here. First, nicotine has
been reported to up-regulate the viral “receptor” angiotensin converting enzyme 2 (ACE2) on
neurons, providing a mechanism for increased SARS CoV2 infectivity and neurotoxicity in
smokers and “vapers” [see Kabbani & Olds 2020]. The nicotinic receptor partial agonists
(lobinaline N-oxides) from the parent award should inhibit this effect of nicotine, and this will be
tested in the first specific aim using immunohistochemistry to evaluate ACE2 expression in
organotypic cultures. Once CNS infection has occurred, coronaviruses cause “excitotoxicity” that
is inhibited by inhibitors of neuronal glutamate /NMDA receptors (NMDARs) [Hasanagic &
Serdeveric, 2020]. This is similar to alcohol withdrawal (AWD) [Stepanyan et al, 2008] and so
should be ameliorated by drugs that prevent neurotoxicity in AWD. Once again, the nicotinic
activity of lobinaline N-oxides may be valuable, but another medication under development by the
company for alcohol use disorder, the aryliminoguanidine, JR220, is even more directly relevant
because it is an inhibitory modulator of the NMDAR [Barron et al, 2012], The neuroprotective
possibilities for these drugs will be evaluated against viral protein neurotoxicity in organotypic
cultures in specific aim 2. The hypothesis is therefore that coronavirus infectivity and neurotoxicity
are enhanced in patients with nicotine and alcohol use disorders, and that both the disorders and
the COVID19 consequences should be inhibited by the medications under development. These
novel therapeutic targets for lobinaline N-oxides and JR220 in COVID-19 infection will strongly
support the therapeutic and commercial value of products from the parent award.
Terms: <2019 novel coronavirus><2019-nCoV><AIDS Virus><Acquired Immune Deficiency Syndrome Virus><Acquired Immunodeficiency Syndrome Virus><Affect><Agonist><Alcohol Chemical Class><Alcohol Drinking><Alcohol consumption><Alcohol withdrawal syndrome><Alcohols><Ammon Horn><Angiotensin Converting Enzyme><Angiotensin I-Converting Enzyme><Angiotensin Receptor><Animal Model><Animal Models and Related Studies><Award><Binding Proteins><CD143 Antigens><CNS infection><COVID-19><COVID-19 epidemic><COVID-19 pandemic><COVID19><COVID19 epidemic><COVID19 pandemic><Carboxycathepsin><Cell Body><Cell surface><Cells><Central Nervous System Infections><Central Nervous System Infectious Disease><Central Nervous System Infectious Disorder><Chronic><Clinical><Common Rat Strains><Complex><Computer software><Cornu Ammonis><Coronaviridae><Coronavirus><DAT dopamine transporter><Development><Diagnostic Findings><Dipeptidyl Peptidase A><Disease><Disease Outbreaks><Disorder><Drugs><EtOH drinking><EtOH use><Exposure to><Fluorescence Light Microscopy><Fluorescence Microscopy><Future><Glutamates><HIV><HIV tat Protein><Heavy Drinking><Hippocampus><Hippocampus (Brain)><Hospital Admission><Hospitalization><Human Immunodeficiency Viruses><Image><Immunohistochemistry><Immunohistochemistry Cell/Tissue><Immunohistochemistry Staining Method><In Vitro><Infection><Kininase A><Kininase II><L-Glutamate><LAV-HTLV-III><Ligand Binding Protein><Ligand Binding Protein Gene><Lung><Lung Respiratory System><Lymphadenopathy-Associated Virus><Mediating><Medication><Memantin><Memantine><Microscopy><N-Methyl-D-Aspartate Receptors><N-Methylaspartate Receptors><NMDA Receptor-Ionophore Complex><NMDA Receptors><NMDA receptor antagonist><Nerve Cells><Nerve Unit><Neural Cell><Neurocyte><Neurologic><Neurological><Neurons><Nicotine><Nicotine Use Disorder><Nicotinic Acetylcholine Receptors><Nicotinic Receptors><Outbreaks><Outcome><Oxides><Parents><Patients><Peptidyl-Dipeptidase A><Pharmaceutic Preparations><Pharmaceutical Preparations><Phenotype><Predisposition><Preparation><Protein Binding><Proteins><Pulmonary Pathology><Rat><Rats Mammals><Rattus><Receptor Protein><Reporting><Respiratory Signs and Symptoms><Route><SARS-CoV-2><SARS-CoV2><SARS-associated coronavirus 2><SARS-coronavirus-2><SARS-related coronavirus 2><Severe acute respiratory syndrome coronavirus 2><Severities><Signs and Symptoms><Site><Smoker><Smoking><Software><Staining method><Stains><Susceptibility><Testing><Therapeutic><Toxic effect><Toxicities><Up-Regulation><Upregulation><Viral><Viral Gene Products><Viral Gene Proteins><Viral Proteins><Viral Receptor><Virus Receptors><Virus-HIV><Wuhan coronavirus><access to alcohol><airway symptom><alcohol abuse therapy><alcohol abuse treatment><alcohol access><alcohol accessibility><alcohol availability><alcohol exposed><alcohol exposure><alcohol ingestion><alcohol intake><alcohol product use><alcohol treatment><alcohol use><alcohol use disorder><alcohol withdrawal><alcoholic beverage consumption><alcoholic drink intake><bound protein><clay><commercialization><corona virus><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><developmental><dopamine transporter><drink heavily><drug/agent><ethanol accessibility><ethanol availability><ethanol consumption><ethanol drinking><ethanol exposed><ethanol exposure><ethanol ingestion><ethanol intake><ethanol product use><ethanol use><ethanol use disorder><ethanol withdrawal><excessive alcohol consumption><excessive alcohol ingestion><excessive alcohol intake><excessive drinking><excessive ethanol ingestion><excitotoxicity><exposed to alcohol><exposed to ethanol><exposure to alcohol><exposure to ethanol><extreme drinking><glutamatergic><heavy alcohol use><hippocampal><imaging><inhibitor><inhibitor/antagonist><lung pathology><model of animal><model organism><neuroinflammation><neuroinflammatory><neuron toxicity><neuronal><neuronal toxicity><neurotoxic><neurotoxicity><new drug target><new druggable target><new pharmacotherapy target><new therapeutic target><new therapy target><nicotine consumption><nicotine inhalation><nicotine use><novel><novel drug target><novel druggable target><novel pharmacotherapy target><novel therapeutic target><novel therapy target><prevent><preventing><pulmonary><pulmonary symptom><receptor><respiratory symptom><respiratory virus><therapeutic candidate><vaper><vaping><virus protein><withdrawal from alcohol>