Document text
Principal Investigator: HAFIZ AHMED
Organization: GLYCOMANTRA, INC.
Fiscal Year: 2022
Award: $300,000
Funding agency: National Institute of Allergy and Infectious Diseases
Project Summary/Abstract
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)-α. 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.
Terms: <(TNF)-α><2019 novel corona virus><2019 novel coronavirus><2019-nCoV><2019-nCoV S protein><2019-nCoV spike glycoprotein><2019-nCoV spike protein><A549><ACE Inhibitors><ACE2><Adult-Onset Diabetes Mellitus><Affinity><Agreement><Alveolar Cell><AngII><Angiotensin I-Converting Enzyme Inhibitors><Angiotensin II><Angiotensin-Converting Enzyme Antagonists><Angiotensin-Converting Enzyme Inhibitors><Animal Model><Animal Models and Related Studies><Animals><Anti-Inflammatories><Anti-Inflammatory Agents><Anti-inflammatory><Antiinflammatories><Antiinflammatory Agents><Antiviral Therapy><Assay><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><Binding><Bioassay><Bioavailability><Biologic Assays><Biologic Availability><Biological Assay><Biological Availability><Biological Markers><Blood><Blood Reticuloendothelial System><CBP-30><CBP-35><CBP35><COVID crisis><COVID epidemic><COVID pandemic><COVID-19><COVID-19 S protein><COVID-19 affected><COVID-19 consequence><COVID-19 crisis><COVID-19 effect><COVID-19 epidemic><COVID-19 global health crisis><COVID-19 global pandemic><COVID-19 health crisis><COVID-19 impact><COVID-19 impacted><COVID-19 infection><COVID-19 pandemic><COVID-19 predisposition><COVID-19 public health crisis><COVID-19 spike glycoprotein><COVID-19 spike protein><COVID-19 susceptibility><COVID-19 therapy><COVID-19 treatment><COVID-19 virus><COVID-19 vulnerability><COVID19><COVID19 S protein><COVID19 crisis><COVID19 epidemic><COVID19 global health crisis><COVID19 global pandemic><COVID19 health crisis><COVID19 infection><COVID19 pandemic><COVID19 public health crisis><COVID19 spike glycoprotein><COVID19 spike protein><COVID19 therapy><COVID19 treatment><COVID19 virus><CV-19><CV19><Cachectin><Carbohydrate-Binding Protein 35><Cell Body><Cell Coat><Cell Culture Techniques><Cells><CoV-2><CoV2><Coronavirus disease 2019 predisposition><Coronavirus disease 2019 susceptibility><Coronavirus disease 2019 vulnerability><Diabetes Mellitus><Drug Therapy><Drugs><Elderly><Engineering><Epithelial Cells><Epsilon-Binding Protein><Fats><Fatty acid glycerol esters><Frequencies><Future><Galactosides><Galectin 3><Glucose tolerance test><Glycans><Glycocalyx><Glycoproteins><Goals><HL-29><HPGF><Health Care Systems><Healthcare Systems><Hepatocyte-Stimulating Factor><High Fat Diet><Human><Hybridoma Growth Factor><Hypertension><IFN-beta 2><IFNB2><IL-6><IL6 Protein><IPGTT><IgE Binding Protein><IgEBP><Immune><Immune response><Immunes><Immunological response><In Vitro><Incidence><Infection><Inflammation><Inflammatory><Insulin Receptor><Insulin Receptor Protein-Tyrosine Kinase><Insulin Resistance><Insulin-Dependent Tyrosine Protein Kinase><Interleukin-6><Ketosis-Resistant Diabetes Mellitus><Kininase II Antagonists><Kininase II Inhibitors><L-29 Lectin><L-31><L-34><L30 Lectin><LGALS3><Lectin><Legal patent><Licensing><Ligands><Liver><Lung><Lung Alveolar Epithelia><Lung Respiratory System><MGI-2><Mac-2 Antigen><Macrophage-2 Antigen><Macrophage-Derived TNF><Maturity-Onset Diabetes Mellitus><Measures><Mediating><Medication><Mice><Mice Mammals><Modern Man><Molecular Interaction><Monocyte-Derived TNF><Morbidity><Morbidity - disease rate><Mucous body substance><Mucus><Murine><Mus><Muscle><Muscle Tissue><Myeloid Differentiation-Inducing Protein><Mφ><NIDDM><Names><Non-Insulin Dependent Diabetes><Non-Insulin-Dependent Diabetes Mellitus><Noninsulin Dependent Diabetes><Noninsulin Dependent Diabetes Mellitus><Obesity><PK/PD><Patents><Pathogenesis><Patients><Persons><Pharmaceutic Preparations><Pharmaceutical Agent><Pharmaceutical Preparations><Pharmaceuticals><Pharmacologic Substance><Pharmacological Substance><Pharmacotherapy><Phase><Phase 1/1b Clinical Trial><Phase I/IB Clinical Trial><Physiologic Availability><Plasmacytoma Growth Factor><Play><Polysaccharides><Population><Prediabetes><Prediabetes syndrome><Prediabetic State><Predisposed to COVID-19><Predisposed to SARS-CoV-2><Predisposed to Severe acute respiratory syndrome coronavirus 2><Production><Proteins><Publications><Pulmonary Body System><Pulmonary Organ System><Receptor Activation><Receptor Protein><Receptor Signaling><Resolution><Respiratory System><Respiratory Tracts><Respiratory tract structure><Rodent><Rodentia><Rodents Mammals><Role><SARS corona virus 2><SARS-CO-V2><SARS-COVID-2><SARS-CoV-2><SARS-CoV-2 S protein><SARS-CoV-2 epidemic><SARS-CoV-2 global health crisis><SARS-CoV-2 global pandemic><SARS-CoV-2 infection><SARS-CoV-2 inhibitor><SARS-CoV-2 pandemic><SARS-CoV-2 predisposition><SARS-CoV-2 spike glycoprotein><SARS-CoV-2 spike protein><SARS-CoV-2 susceptibility><SARS-CoV-2 therapy><SARS-CoV-2 treatment><SARS-CoV-2 vulnerability><SARS-CoV2><SARS-CoV2 S protein><SARS-CoV2 epidemic><SARS-CoV2 infection><SARS-CoV2 pandemic><SARS-CoV2 spike glycoprotein><SARS-CoV2 spike protein><SARS-associated corona virus 2><SARS-associated coronavirus 2><SARS-coronavirus-2><SARS-coronavirus-2 epidemic><SARS-coronavirus-2 pandemic><SARS-related corona virus 2><SARS-related coronavirus 2><SARSCoV2><Scientific Publication><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 CoV 2 epidemic><Severe Acute Respiratory Syndrome CoV 2 pandemic><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 corona virus 2><Severe acute respiratory syndrome coronavirus 2><Severe acute respiratory syndrome coronavirus 2 S protein><Severe acute respiratory syndrome coronavirus 2 epidemic><Severe acute respiratory syndrome coronavirus 2 infection><Severe acute respiratory syndrome coronavirus 2 inhibitor><Severe acute respiratory syndrome coronavirus 2 pandemic><Severe acute respiratory syndrome coronavirus 2 predisposition><Severe acute respiratory syndrome coronavirus 2 spike glycoprotein><Severe acute respiratory syndrome coronavirus 2 spike protein><Severe acute respiratory syndrome coronavirus 2 susceptibility><Severe acute respiratory syndrome coronavirus 2 vulnerability><Severe acute respiratory syndrome related corona virus 2><Slow-Onset Diabetes Mellitus><Source><Stable Diabetes Mellitus><T-Cells><T-Lymphocyte><T2 DM><T2D><T2DM><TNF><TNF A><TNF Alpha><TNF gene><TNF-α><TNFA><TNFα><Technology><Therapeutic><Thick><Thickness><Toxic effect><Toxicities><Transgenic Mice><Tumor Necrosis Factor><Tumor Necrosis Factor-alpha><Type 2 Diabetes Mellitus><Type 2 diabetes><Type II Diabetes Mellitus><Type II diabetes><Vascular Hypertensive Disease><Vascular Hypertensive Disorder><Viral><Viral Burden><Viral Diseases><Viral Load><Viral Load result><Virus><Virus Diseases><Wuhan coronavirus><adiposity><adult onset diabetes><advanced age><alveolar epithelium><angiotensin converting enzyme 2><angiotensin converting enzyme II><antagonist><anti-viral therapy><antiinflammatory><base><bio-markers><biologic marker><biomarker><block SARS-CoV-2><block severe acute respiratory syndrome coronavirus 2><cell bank><cell culture><cell cultures><corona virus disease 2019><corona virus disease 2019 epidemic><corona virus disease 2019 pandemic><coronavirus disease 2019><coronavirus disease 2019 S protein><coronavirus disease 2019 consequence><coronavirus disease 2019 crisis><coronavirus disease 2019 effect><coronavirus disease 2019 epidemic><coronavirus disease 2019 global health crisis><coronavirus disease 2019 global pandemic><coronavirus disease 2019 health crisis><coronavirus disease 2019 impact><coronavirus disease 2019 infection><coronavirus disease 2019 pandemic><coronavirus disease 2019 public health crisis><coronavirus disease 2019 spike glycoprotein><coronavirus disease 2019 spike protein><coronavirus disease 2019 therapy><coronavirus disease 2019 treatment><coronavirus disease 2019 virus><coronavirus disease crisis><coronavirus disease epidemic><coronavirus disease pandemic><coronavirus disease-19><coronavirus disease-19 global pandemic><coronavirus disease-19 impact><coronavirus disease-19 pandemic><coronavirus disease-19 virus><coronavirus infectious disease-19><corpulence><cytokine><cytokine release syndrome><cytokine storm><diabetes><diabetic><diabetic patient><dietary><drug treatment><drug/agent><elders><experiment><experimental research><experimental study><fasting glucose><geriatric><glucose tolerance><hCoV19><hepatic body system><hepatic organ system><high blood pressure><host response><humanized mice><humanized mouse><hyperpiesia><hyperpiesis><hypertensive><hypertensive disease><hypertensive disorder><immune system response><immunoresponse><improved><infected with COVID-19><infected with COVID19><infected with SARS-CoV-2><infected with SARS-CoV2><infected with coronavirus disease 2019><infected with severe acute respiratory syndrome coronavirus 2><inhibit SARS-CoV-2><inhibit severe acute respiratory syndrome coronavirus 2><insulin resistant><insulin sensitivity><insulin signaling><insulin tolerance><interferon beta 2><intraperitoneal glucose tolerance test><ketosis resistant diabetes><knock-down><knockdown><late life><later life><macrophage><maturity onset diabetes><model of animal><model organism><mortality><mouse model><mucous><murine model><muscular><nCoV2><novel><older adult><older person><pandemic><pandemic disease><pharmacokinetics and pharmacodynamics><pre-diabetes><pre-diabetic><prediabetic><predisposed to Coronavirus disease 2019><primary end point><primary endpoint><pulmonary><receptor><restoration><secondary end point><secondary endpoint><senior citizen><severe acute respiratory syndrome coronavirus 2 global health crisis><severe acute respiratory syndrome coronavirus 2 global pandemic><severe acute respiratory syndrome coronavirus 2 therapy><severe acute respiratory syndrome coronavirus 2 treatment><social role><susceptible to COVID-19><susceptible to Coronavirus disease 2019><susceptible to SARS-CoV-2><susceptible to Severe acute respiratory syndrome coronavirus 2><thymus derived lymphocyte><treat COVID-19><treat COVID19><treat SARS-CoV-2><treat coronavirus disease 2019><treat severe acute respiratory syndrome coronavirus 2><type 2 DM><type II DM><type two diabetes><viral infection><viral infectious disease treatment><virus infection><virus-induced disease>