The COVID-19, caused by the severe acute respiratory syndrome coronavirus 2 (SARSCoV-2), is a global pandemic with catastrophic consequences for healthcare systems and populations. The increased morbidity and mortality in older persons and those with diabetes (12-22%) and hypertension (23.7-30%) is particularly concerning due to high incidence of diabetes throughout the world. The angiotensin-converting enzyme 2 (ACE2) receptor serves as a high affinity receptor for SARSCoV-2 to enter the lungs. Interestingly, patients with diabetes, who are treated with ACE inhibitor and angiotensin II type-I receptor blocker, highly express ACE2 making them more susceptible to COVID-19. For infection and pathogenesis, virus needs to attach and penetrate a thick glycan rich mucus and glycocalyx before binding its entry-receptor and galectin-3 (Gal3) is believed to play a role in the enhanced attachment of SARSCoV-2 through binding to the spike glycoprotein. Gal3 promotes viral infections and enhances of pro-inflammatory cytokines such as interleukin (IL)-6, tumor necrosis factor (TNF)-a. We confirmed Gal3 binding to SARSCoV-2 spike glycoprotein. Interestingly, increased levels of Gal3 are associated with prediabetes, diabetes, and hypertension. Gal3 binds also directly to the insulin receptor (IR) and inhibits downstream IR signaling promoting obesity-mediated inflammation (macrophage-derived Gal3) and insulin resistance in type 2 diabetes (T2D). These fundamental observations elucidate a novel role of Gal3 that promotes viral infection and uncontrolled release of pro-inflammatory/anti- inflammatory cytokines and suggest that specific inhibition of Gal3 may represent a promising therapeutic strategy not only treat COVID-19, but also COVID-19 impacted diabetic patients. Our scientific premise is that we have developed a very potent Gal3 antagonist, named TFD100, from a natural dietary source (PNAS publication PMID: 23479624). In our preliminary studies, TFD100 inhibited replication of SARSCoV-2. TFD100 reversed Gal3 mediated inhibition of IR activation. TFD100 also decreased fasting glucose and improved glucose tolerance and insulin sensitivity. Here, we propose to investigate the therapeutic utilities of TFD100 for treating COVID-19 and COVID-19 impacted T2D in a relevant COVID-19 "humanized" mouse model (human ACE-2 transgenic mice). Following drug treatment of SARSCoV-2 infected mice, viral load (primary endpoint) and resolution of dysregulated inflammation (secondary endpoint) will be measured. To investigate TFD100's ability to intervene COVID-19 impacted T2D in hACE-2 mice, obese- induced T2D will be made first in these mice with high fat diet followed by SARSCoV-2 infection. Following drug treatment, glucose and insulin tolerance as well as viral load (primary endpoints) will be measured. For other endpoints, resolution of host-response as dysregulated inflammation (cytokine storm) and restoration of insulin signaling will be measured by the frequency of pro-inflammatory/anti-inflammatory biomarkers (Gal3, ACE-2, and other proteins) in blood, lung, liver, fat, and muscle. This also includes determination of changes in pro/anti-inflammatory immune cell frequencies denoted by polarization of macrophages and helper-T (Th) cells. Gal3 inhibition is anticipated to be a significant advancement in the arsenal against SARSCoV-2 impacted T2D, and possibly SARSCoV-2 infection as an antiviral therapy.
Public Health Relevance Statement: Project Narrative Galectin-3 (Gal3) not only promotes insulin resistance of type 2 diabetes (T2D), but also is involved in the viral attachment and cytokine storm. The objective of this project is to use Gal3 antagonist to treat COVID-19 and COVID-19 impacted T2D.
Project Terms: advanced age; elders; geriatric; late life; later life; older adult; older person; senior citizen; Elderly; ACE Inhibitors; Angiotensin I-Converting Enzyme Inhibitors; Angiotensin-Converting Enzyme Antagonists; Kininase II Antagonists; Kininase II Inhibitors; Angiotensin-Converting Enzyme Inhibitors; Animals; Anti-Inflammatories; Anti-inflammatory; Antiinflammatories; Antiinflammatory Agents; antiinflammatory; Anti-Inflammatory Agents; Biological Assay; Assay; Bioassay; Biologic Assays; Biological Availability; Bioavailability; Physiologic Availability; Blood; Blood Reticuloendothelial System; Cell Culture Techniques; cell culture; cell cultures; Cells; Cell Body; Diabetes Mellitus; diabetes; Non-Insulin-Dependent Diabetes Mellitus; Adult-Onset Diabetes Mellitus; Ketosis-Resistant Diabetes Mellitus; Maturity-Onset Diabetes Mellitus; NIDDM; Non-Insulin Dependent Diabetes; Noninsulin Dependent Diabetes; Noninsulin Dependent Diabetes Mellitus; Slow-Onset Diabetes Mellitus; Stable Diabetes Mellitus; T2 DM; T2D; T2DM; Type 2 Diabetes Mellitus; Type 2 diabetes; Type II Diabetes Mellitus; Type II diabetes; adult onset diabetes; ketosis resistant diabetes; maturity onset diabetes; type 2 DM; type II DM; type two diabetes; Pharmacotherapy; Drug Therapy; drug treatment; Pharmaceutical Preparations; Drugs; Medication; Pharmaceutic Preparations; drug/agent; Engineering; Epithelial Cells; Fatty acid glycerol esters; Fats; Future; Glucose tolerance test; IPGTT; intraperitoneal glucose tolerance test; Glycoproteins; glycosylation; Metabolic Glycosylation; Goals; Healthcare Systems; Health Care Systems; Human; Modern Man; Hypertension; Vascular Hypertensive Disease; Vascular Hypertensive Disorder; high blood pressure; hyperpiesia; hyperpiesis; hypertensive disease; hypertensive disorder; In Vitro; Incidence; Infection; Inflammation; Insulin Resistance; insulin resistant; Interleukin-6; B cell differentiation factor; B cell stimulating factor 2; B-Cell Differentiation Factor; B-Cell Differentiation Factor-2; B-Cell Stimulatory Factor-2; BCDF; BSF-2; BSF2; HPGF; Hepatocyte-Stimulating Factor; Hybridoma Growth Factor; IFN-beta 2; IFNB2; IL-6; IL6 Protein; MGI-2; Myeloid Differentiation-Inducing Protein; Plasmacytoma Growth Factor; interferon beta 2; Ligands; Liver; hepatic body system; hepatic organ system; Lung; Lung Respiratory System; pulmonary; Macrophage; MÏ; Transgenic Mice; Morbidity - disease rate; Morbidity; mortality; Mucous body substance; Mucus; mucous; Mus; Mice; Mice Mammals; Murine; Muscle; Muscle Tissue; muscular; Persons; Names; name; named; naming; Obesity; adiposity; corpulence; Legal patent; Patents; Patients; Polysaccharides; Glycans; Production; Proteins; Publications; Scientific Publication; Insulin Receptor; Insulin Receptor Protein-Tyrosine Kinase; Insulin-Dependent Tyrosine Protein Kinase; Respiratory System; Respiratory tract structure; Pulmonary Body System; Pulmonary Organ System; Respiratory Tracts; Rodent; Rodentia; Rodents Mammals; 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Angiotensin II Type 1 Receptor; angiotensin II type I receptor; receptor; Receptor Protein; insulin tolerance; Animal Model; Animal Models and Related Studies; model of animal; Toxic effect; Toxicities; Galactose Binding Lectin; D-Galactoside-Binding Lectin; Galaptins; Galectins; S-Type Lectins; beta-D-Galactosyl-Specific Lectin; beta-Galactoside Binding Lectin; novel; Agreement; Pathogenesis; TNF gene; (TNF)-a; Cachectin; Macrophage-Derived TNF; Monocyte-Derived TNF; TNF; TNF A; TNF Alpha; TNF-a; TNFA; TNFa; Tumor Necrosis Factor; Tumor Necrosis Factor-alpha; cell bank; insulin sensitivity; Molecular Interaction; Binding; Pharmaceutical Agent; Pharmaceuticals; Pharmacological Substance; pharmaceutical; Pharmacologic Substance; Thickness; Thick; Affinity; Receptor Activation; Receptor Signaling; Resolution; resolutions; Alveolar Cell; pandemic disease; pandemic; knockdown; knock-down; insulin signaling; Population; murine model; mouse model; A549; bio-markers; biologic marker; biomarker; Biological Markers; diabetic patient; fasting glucose; humanized mice; humanized mouse; High Fat Diet; experiment; experimental research; experiments; experimental study; cytokine storm; cytokine release syndrome; secondary end point; secondary endpoint; primary end point; primary endpoint; PK/PD; pharmacokinetics and pharmacodynamics; COVID19; CV-19; CV19; corona virus disease 2019; coronavirus disease 2019; coronavirus disease-19; coronavirus infectious disease-19; COVID-19; 2019 novel corona virus; 2019 novel coronavirus; COVID-19 virus; COVID19 virus; CoV-2; CoV2; SARS corona virus 2; SARS-CO-V2; SARS-COVID-2; SARS-CoV-2; SARS-CoV2; SARS-associated corona virus 2; SARS-associated coronavirus 2; SARS-coronavirus-2; SARS-related corona virus 2; SARS-related coronavirus 2; SARSCoV2; Severe Acute Respiratory Coronavirus 2; Severe Acute Respiratory Distress Syndrome CoV 2; Severe Acute Respiratory Distress Syndrome Corona Virus 2; Severe Acute Respiratory Distress Syndrome Coronavirus 2; Severe Acute Respiratory Syndrome CoV 2; Severe Acute Respiratory Syndrome-associated coronavirus 2; Severe Acute Respiratory Syndrome-related coronavirus 2; Severe acute respiratory syndrome associated corona virus 2; Severe acute respiratory syndrome coronavirus 2; Severe acute respiratory syndrome related corona virus 2; Wuhan coronavirus; coronavirus disease 2019 virus; coronavirus disease-19 virus; hCoV19; nCoV2; 2019-nCoV; COVID crisis; COVID epidemic; COVID pandemic; COVID-19 crisis; COVID-19 epidemic; COVID-19 global health crisis; COVID-19 global pandemic; COVID-19 health crisis; COVID-19 public health crisis; COVID19 crisis; COVID19 epidemic; COVID19 global health crisis; COVID19 global pandemic; COVID19 health crisis; COVID19 pandemic; COVID19 public health crisis; SARS-CoV-2 epidemic; SARS-CoV-2 global health crisis; SARS-CoV-2 global pandemic; SARS-CoV-2 pandemic; SARS-CoV2 epidemic; SARS-CoV2 pandemic; SARS-coronavirus-2 epidemic; SARS-coronavirus-2 pandemic; Severe Acute Respiratory Syndrome CoV 2 epidemic; 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