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Principal Investigator: TIMOTHY A HAYSTEAD
Organization: EYDIS BIO, INC.
Fiscal Year: 2021
Award: $309,288
Funding agency: National Heart Lung and Blood Institute
PROJECT SUMMARY/ABSTRACT
The recent pandemic of novel coronavirus, COVID-19, has had a devastating effect on the health and well-being
of individuals across the globe, including over 3.1 million confirmed infected so far, and a monumental impact
on global healthcare systems and economies at large. In the US, over 1,000,000 cases have been confirmed to
date, including over 60,000 deaths, and some studies estimate that COVID-19 could cost the US healthcare
system $556 billion over the next two years. There are currently no approved treatments for COVID-19, and
many current efforts are expectedly targeting the viral mechanisms of disease. However, evidence from COVID-
19 patients has identified hyperinflammation as a major contributor to disease progression and outcomes, and
reduction of hyperinflammatory mediators such as TNF, IL-1 and IL-6 has become a novel therapeutic axis for
the treatment of COVID-19 patients. Thus, various branded anti-cytokine immunomodulators (e.g., anti-IL-1 and
anti-IL-6 biologics) are currently undergoing clinical trials to treat complications of COVID-19 disease such as
acute respiratory distress syndrome (ARDS), cytokine release syndrome, and pneumonia. However, all of these
therapeutics remove all target cytokine expression, dampening immune-viral detection leading to disease
progression. Therefore, there exists an unmet need for an orally bioavailable small molecule therapeutic that can
taper inflammatory cytokines to normal levels in an active COVID-19 infection. Our preclinical work has identified
TGFβ-activated kinase 1 (TAK1), as a key signaling element within the TNF-mediated proinflammatory response
pathway. Given recent clinical data identifying TNF as the primary player in the initiation of the COVID-19 induced
cytokine storm, we posit that TAK1 can be targeted to prevent or greatly reduce pulmonary hyperinflammation
seen in COVID-19 patients. Our recent discovery of the takinib scaffold and subsequent medicinal chemistry
efforts have led to the development of the first orally bioavailable, highly selective and potent (IC50 ~2.5nM)
inhibitor of TAK1, HS-276. To obtain proof-of-concept for development of TAK1 as target for COVID-19 induced
ARDS, we propose the following Specific Aims: Aim 1 – Establish the therapeutic efficacy of HS-276 to reduce
inflammation in the LPS-induced pulmonary inflammatory model. Milestone: Define the therapeutic window of
HS-276 in the LPS-induced pulmonary inflammatory model. Aim 2 – Evaluate the in vitro and in vivo effects of
TAK1 inhibition with HS-276 in response to COVID-19 spike protein (S-protein) challenge. Milestone: Establish
that HS-276 blocks S-protein induced TNF expression by ≥50% compared to vehicle-treated in vitro. Aim 3 –
Determine the efficacy of HS-276 to reduce viral-induced ARDS in a SARS-CoV-2 model. Milestone: Expand
preclinical indication/efficacy data of HS-276 to treat viral induced pulmonary hyperinflammation. Achieving the
Specific Aims above will provide the necessary data for us to pursue a Phase II NIH SBIR application to fund
pre-IND-enabling studies en route to IND-enabling studies.
Terms: <(TNF)-α><2019 novel corona virus><2019 novel coronavirus><2019-nCoV><2019-nCoV S protein><2019-nCoV spike glycoprotein><2019-nCoV spike protein><ARDS><ATP-protein phosphotransferase><Acute><Acute Respiratory Distress><Acute Respiratory Distress Syndrome><Adult ARDS><Adult RDS><Adult Respiratory Distress Syndrome><Adverse reactions><Alveolar><Animal Model><Animal Models and Related Studies><Animals><Anti-Inflammatories><Anti-Inflammatory Agents><Anti-Tumor Necrosis Factor Therapy><Anti-inflammatory><Antiinflammatories><Antiinflammatory Agents><Antiinflammatory Effect><Antiviral Agents><Antiviral Drugs><Antivirals><Atrophic Arthritis><Autoimmune Diseases><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><Bioavailable><Biological><Blood Neutrophil><Blood Polymorphonuclear Neutrophil><Bone-Derived Transforming Growth Factor><COVID associated ARDS><COVID associated acute respiratory distress syndrome><COVID crisis><COVID epidemic><COVID induced ARDS><COVID induced acute respiratory distress syndrome><COVID infected patient><COVID pandemic><COVID patient><COVID positive patient><COVID related ARDS><COVID related acute respiratory distress syndrome><COVID-19><COVID-19 S protein><COVID-19 associated ARDS><COVID-19 associated acute respiratory distress syndrome><COVID-19 associated cytokine storm><COVID-19 crisis><COVID-19 cytokine storm><COVID-19 epidemic><COVID-19 global health crisis><COVID-19 global pandemic><COVID-19 health crisis><COVID-19 induced ARDS><COVID-19 induced acute respiratory distress syndrome><COVID-19 induced cytokine storm><COVID-19 infected patient><COVID-19 infection><COVID-19 pandemic><COVID-19 patient><COVID-19 positive patient><COVID-19 public health crisis><COVID-19 related ARDS><COVID-19 related acute respiratory distress syndrome><COVID-19 related cytokine storm><COVID-19 spike glycoprotein><COVID-19 spike protein><COVID-19 therapy><COVID-19 treatment><COVID-19 virus><COVID-19/ARDS><COVID-19/acute respiratory distress syndrome><COVID/ARDS><COVID/acute respiratory distress syndrome><COVID19><COVID19 S protein><COVID19 associated ARDS><COVID19 associated acute respiratory distress syndrome><COVID19 crisis><COVID19 epidemic><COVID19 global health crisis><COVID19 global pandemic><COVID19 health crisis><COVID19 induced ARDS><COVID19 induced acute respiratory distress syndrome><COVID19 infection><COVID19 pandemic><COVID19 patient><COVID19 positive patient><COVID19 public health crisis><COVID19 related ARDS><COVID19 related acute respiratory distress syndrome><COVID19 spike glycoprotein><COVID19 spike protein><COVID19 therapy><COVID19 treatment><COVID19 virus><COVID19/ARDS><COVID19/acute respiratory distress syndrome><CSAID-Binding Protein 1><CSAID-Binding Protein 2><CSBP2><CV-19><CV19><Cachectin><Cachectin Receptors><Cell Body><Cell Communication and Signaling><Cell Nucleus><Cell Signaling><Cells><Cessation of life><Characteristics><Chemotactic Cytokines><Chronic><Chronic Disease><Chronic Illness><Clinical><Clinical Data><Clinical Trials><CoV emergence><CoV-2><CoV2><Cytokine Signal Transduction><Cytokine Signaling><Cytokine-Suppressive Antiinflammatory Drug-Binding Protein 1><Cytokine-Suppressive Antiinflammatory Drug-Binding protein 2><Da Nang Lung><Data><Death><Development><Disease><Disease Outcome><Disease Progression><Disorder><Dose><Dropsy><Drugs><Edema><Elements><Extracellular Signal-Regulated Kinase Gene><Fibrosis><Funding><Future><HPGF><Health><Health Care Systems><Healthcare Systems><Hepatocyte-Stimulating Factor><Herd Immunity><Homologous Chemotactic Cytokines><Human><Hybridoma Growth Factor><Hydrops><IFN-beta 2><IFNB2><IL-1><IL-6><IL1><IL6 Protein><IMiD><Immune><Immune modulatory therapeutic><Immune response><Immune system><Immunes><Immunological response><Immunomodulators><In Vitro><Individual><Infection><Inflammation><Inflammatory><Inflammatory Response><Injectable><Innate Immunity><Intercrines><Interleukin I><Interleukin-1><Interleukin-6><Intervention><Intervention Strategies><Intracellular Communication and Signaling><Invaded><Kinase Family Gene><Kinases><Lung><Lung Respiratory System><Lung diseases><Lymphocyte-Stimulating Hormone><MAP Kinase Gene><MAPK><MAPK14><MAPK14 Mitogen-Activated Protein Kinase><MAPK14 gene><MERS corona virus><MERS coronavirus><MERS virus><MERS-CoV><MGI-2><Macrophage Cell Factor><Macrophage-Derived TNF><Marrow Neutrophil><Mediating><Mediator><Mediator of Activation><Mediator of activation protein><Medication><Medicinal Chemistry><Middle East Respiratory Syndrome Corona Virus><Middle East Respiratory Syndrome Coronavirus><Middle East Respiratory Syndrome Virus><Middle East Respiratory Syndrome-CoV><Middle Eastern Respiratory Syndrome Corona virus><Middle Eastern Respiratory Syndrome Coronavirus><Middle Eastern Respiratory Syndrome Virus><Middle Eastern Respiratory Syndrome-CoV><Milk Growth Factor><Mitogen-Activated Protein Kinase 14><Mitogen-Activated Protein Kinase Gene><Modeling><Modern Man><Molecular><Monocyte-Derived TNF><Mxi2><Myeloid Differentiation-Inducing Protein><Mφ><NIH><National Institutes of Health><Native Immunity><Natural Immunity><Neutrophilic Granulocyte><Neutrophilic Leukocyte><Non-Specific Immunity><Nonspecific Immunity><Nuclear><Nucleus><Oral><Outcome><PBMC><Pathway interactions><Patients><Peripheral Blood Mononuclear Cell><Personal Satisfaction><Pharmaceutic Chemistry><Pharmaceutic Preparations><Pharmaceutical Chemistry><Pharmaceutical Preparations><Phase><Phosphotransferase Gene><Phosphotransferases><Physiologic><Physiological><Plasmacytoma Growth Factor><Platelet Transforming Growth Factor><Pneumonia><Polymorphonuclear Cell><Polymorphonuclear Leukocytes><Polymorphonuclear Neutrophils><Prevention><Protein Kinase><Proteins><Public Health><Pulmonary Diseases><Pulmonary Disorder><QOC><Quality of Care><Regimen><Respiratory Disease><Respiratory System Disease><Respiratory System Disorder><Rheumatoid Arthritis><Risk><Role><Route><SAPK2A><SARS Virus><SARS corona virus><SARS corona virus 2><SARS coronavirus><SARS-Associated Coronavirus><SARS-CoV><SARS-CoV-2><SARS-CoV-2 S protein><SARS-CoV-2 associated ARDS><SARS-CoV-2 associated acute respiratory distress syndrome><SARS-CoV-2 associated cytokine storm><SARS-CoV-2 cytokine storm><SARS-CoV-2 epidemic><SARS-CoV-2 global health crisis><SARS-CoV-2 global pandemic><SARS-CoV-2 induced ARDS><SARS-CoV-2 induced acute respiratory distress syndrome><SARS-CoV-2 induced cytokine storm><SARS-CoV-2 infected patient><SARS-CoV-2 infection><SARS-CoV-2 pandemic><SARS-CoV-2 patient><SARS-CoV-2 positive patient><SARS-CoV-2 related ARDS><SARS-CoV-2 related acute respiratory distress syndrome><SARS-CoV-2 related cytokine storm><SARS-CoV-2 spike glycoprotein><SARS-CoV-2 spike protein><SARS-CoV-2 therapy><SARS-CoV-2 treatment><SARS-CoV-2/ARDS><SARS-CoV-2/acute respiratory distress syndrome><SARS-CoV2><SARS-CoV2 S protein><SARS-CoV2 epidemic><SARS-CoV2 infection><SARS-CoV2 pandemic><SARS-CoV2 spike glycoprotein><SARS-CoV2 spike protein><SARS-Related Coronavirus><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><SBIR><SIS cytokines><STTR><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 Virus><Severe Acute Respiratory Syndrome corona virus><Severe Acute Respiratory Syndrome coronavirus><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 pandemic><Severe acute respiratory syndrome coronavirus 2 spike glycoprotein><Severe acute respiratory syndrome coronavirus 2 spike protein><Severe acute respiratory syndrome related corona virus 2><Severity of illness><Shock Lung><Signal Pathway><Signal Transduction><Signal Transduction Systems><Signaling><Small Business Innovation Research><Small Business Innovation Research Grant><Small Business Technology Transfer Research><Stiff lung><Stress-Activated Protein Kinase 2A><T Helper Factor><TGF B><TGF-beta><TGF-β><TGFbeta><TGFβ><TNF><TNF A><TNF Alpha><TNF Receptor Family Protein><TNF Receptor Superfamily><TNF Receptors><TNF gene><TNF-α><TNFA><TNFR><TNFα><Therapeutic><Time><Transforming Growth Factor beta><Transforming Growth Factor-Beta Family Gene><Transphosphorylases><Treatment Efficacy><Tumor Necrosis Factor><Tumor Necrosis Factor Receptor><Tumor Necrosis Factor Receptor Family><Tumor Necrosis Factor Receptor Superfamily><Tumor Necrosis Factor-alpha><United States National Institutes of Health><Vaccines><Viral><Viral Diseases><Virus><Virus Diseases><Work><Wuhan coronavirus><acquired immunity><allergic/immunologic body system><allergic/immunologic organ system><anti-TNF therapy><anti-TNF-alpha therapy><anti-inflammatory effect><anti-viral agents><anti-viral drugs><anti-virals><antiinflammatory><autoimmune condition><autoimmune disorder><bacteria pathogen><bacterial pathogen><base><biological signal transduction><chemoattractant cytokine><chemokine><chronic disorder><co-morbid><co-morbidity><comorbidity><corona virus disease 2019><corona virus disease 2019 epidemic><corona virus disease 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syndrome><coronavirus disease 2019 related cytokine storm><coronavirus disease 2019 spike glycoprotein><coronavirus disease 2019 spike protein><coronavirus disease 2019 therapy><coronavirus disease 2019 treatment><coronavirus disease 2019 virus><coronavirus disease 2019/ARDS><coronavirus disease 2019/acute respiratory distress syndrome><coronavirus disease associated ARDS><coronavirus disease associated acute respiratory distress syndrome><coronavirus disease crisis><coronavirus disease epidemic><coronavirus disease induced ARDS><coronavirus disease induced acute respiratory distress syndrome><coronavirus disease infected patient><coronavirus disease pandemic><coronavirus disease patient><coronavirus disease positive patient><coronavirus disease related ARDS><coronavirus disease related acute respiratory distress syndrome><coronavirus disease/ARDS><coronavirus disease/acute respiratory distress syndrome><coronavirus emergence><coronavirus patient><cost><cytokine><cytokine release syndrome><cytokine storm><develop therapy><developmental><disease of the lung><disease severity><disorder of the lung><drug/agent><efficacy testing><emergent CoV><emergent corona virus><emergent coronavirus><emerging CoV><emerging corona virus><emerging coronavirus><glycogen synthase a kinase><hCoV19><host response><human model><hydroxyalkyl protein kinase><immune modulating agents><immune modulating drug><immune modulating therapeutics><immune modulators><immune modulatory agents><immune modulatory drugs><immune system response><immunomodulating agents><immunomodulatory agents><immunomodulatory drugs><immunomodulatory therapeutics><immunoresponse><improved><in vivo><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><infection risk><inflammation marker><inflammatory marker><inhibitor><inhibitor/antagonist><innovate><innovation><innovative><interferon beta 2><intervention development><intervention efficacy><interventional strategy><lung disorder><lung function><lymphocyte activating factor><macrophage><model of animal><model of human><model organism><nCoV><nCoV2><neutrophil><new CoV><new corona virus><new coronavirus><new drug treatments><new drugs><new therapeutic approach><new therapeutic intervention><new therapeutic strategies><new therapeutics><new therapy><new therapy approaches><next generation therapeutics><novel><novel CoV><novel corona virus><novel coronavirus><novel drug treatments><novel drugs><novel therapeutic approach><novel therapeutic intervention><novel therapeutic strategies><novel therapeutics><novel therapy><novel therapy approach><p38><p38 MAP Kinase><p38 MAPK Gene><p38 Mitogen Activated Protein Kinase><p38 Protein Kinase><p38 SAPK><p38-Alpha><p38Alpha><pandemic><pandemic disease><pathogen><pathogen exposure><pathogenic bacteria><pathogenic virus><pathway><patient infected with COVID><patient infected with COVID-19><patient infected with SARS-CoV-2><patient infected with coronavirus disease><patient infected with coronavirus disease 2019><patient infected with severe acute respiratory syndrome coronavirus 2><patient with COVID><patient with COVID-19><patient with COVID19><patient with SARS-CoV-2><patient with coronavirus disease><patient with coronavirus disease 2019><patient with severe acute respiratory distress syndrome coronavirus 2><phosphorylase b kinase kinase><pre-clinical><preclinical><prevent><preventing><pulmonary><pulmonary function><response><rheumatic arthritis><scaffold><scaffolding><severe acute respiratory syndrome coronavirus 2 associated ARDS><severe acute respiratory syndrome coronavirus 2 associated acute respiratory distress syndrome><severe acute respiratory syndrome coronavirus 2 associated cytokine storm><severe acute respiratory syndrome coronavirus 2 cytokine storm><severe acute respiratory syndrome coronavirus 2 global health crisis><severe acute respiratory syndrome coronavirus 2 global pandemic><severe acute respiratory syndrome coronavirus 2 induced ARDS><severe acute respiratory syndrome coronavirus 2 induced acute respiratory distress syndrome><severe acute respiratory syndrome coronavirus 2 induced cytokine storm><severe acute respiratory syndrome coronavirus 2 infected patient><severe acute respiratory syndrome coronavirus 2 patient><severe acute respiratory syndrome coronavirus 2 positive patient><severe acute respiratory syndrome coronavirus 2 related ARDS><severe acute respiratory syndrome coronavirus 2 related acute respiratory distress syndrome><severe acute respiratory syndrome coronavirus 2 related cytokine storm><severe acute respiratory syndrome coronavirus 2 therapy><severe acute respiratory syndrome coronavirus 2 treatment><severe acute respiratory syndrome coronavirus 2/ARDS><severe acute respiratory syndrome coronavirus 2/acute respiratory distress syndrome><severe acute respiratory syndrome-CoV><side effect><small molecule inhibitor><small molecule therapeutics><social role><targeted drug therapy><targeted drug treatments><targeted therapeutic><targeted therapeutic agents><targeted therapy><targeted treatment><therapeutic efficacy><therapeutic target><therapy development><therapy efficacy><therapy optimization><treat COVID-19><treat COVID19><treat SARS-CoV-2><treat coronavirus disease 2019><treat severe acute respiratory syndrome coronavirus 2><treatment development><treatment optimization><treatment strategy><viral detection><viral infection><viral pathogen><virus detection><virus infection><virus pathogen><virus-induced disease><well-being><wellbeing><wet lung>