First-in-class small molecules that enhance lung barrier function during acute respiratory distress syndrome(ARDS) as potential therapeutics for COVID-19PA-20-260, R43 Phase I SBIRPI: Frederick M. Ausubel Infection by SARS-CoV-2 can lead to highly lethal acute respiratory distress syndrome (ARDS). In ARDS,inflammatory-mediated processes cause a breakdown of tight and adherens junctions in the alveolar capillaryendothelium as well as tight junctions in the alveolar epithelium. This allows fluid, serum proteins, and immunecells to leak out of alveolar capillaries into lung interstitial tissues and then through the alveolar epithelium intothe alveolar airway. There are no therapeutics approved for ARDS that directly target tight and adherensjunctions, even though accumulating evidence suggests that therapeutics that shore up these junctions could behighly efficacious for ARDS patients. To address this unmet need, Artus Therapeutics is developing noveltherapeutics that directly enhance both epithelial and endothelial barrier function in the lungs. Artus's leadcompound, ARTX-2, is a low molecular weight orally available molecule inspired by the natural gut metaboliteUrolithin A. Oral administration of ARTX-2 decreases vascular leakage into lung tissue in mice treated with LPSto induce pulmonary inflammation. ARTX-2 also induces the upregulation of the endothelial junction protein VE-cadherin in mouse lungs. In endothelial cell cultures, ARTX-2 upregulates VE-cadherin and blocks LPS-elicitedpermeability. With respect to epithelial barrier function, ARTX-2 up-regulates several tight junction proteins anddecreases permeability of intestinal epithelial cells. Oral administration of ARTX-2 dramatically mitigatessymptoms in mouse models of ulcerative colitis by restoring gut epithelial barrier function. Further, ARTX-2blocks LPS-elicited inflammatory cytokines including IL-6 and TNF-a in both LPS-treated mice and in LPS-treated bone marrow derived macrophages. From these data, it appears that ARTX-2 may be efficacious in thetreatment of COVID-19 patients because it may enhance both lung endothelial and lung epithelial barrier functionand decrease the levels of inflammatory cytokines without being immunosuppressive. In addition to the leadcompound ARTX-2, 44 ARTX-2 analogs have been synthesized for lead optimization studies. Two specific aimstest the hypotheses that ARTX-2 will decrease permeability in lung epithelium as well as in vascular endothelium,will be efficacious in murine LPS-elicited and viral infection-elicited ARDS models, and that particular ARTX-2analogs will be more potent than ARTX-2. In Aim 1, we propose to test the potency of 44 ARTX-2 analogs incomparison to ARTX-2 in upregulating the expression of tight junction proteins and VE-cadherin in lung epithelialand lung endothelial cell cultures. The 5 most potent analogs will be prioritized for further study in Aim 2. In Aim2, we will test the 5 prioritized analogs from Aim 1 to determine if any are more potent than ARTX-2 in LPS-elicited and viral infection-elicited mouse ARDS models. Successful completion of the proposed studies will resultin the identification of 2-3 new chemical entities (NCEs) that are highly efficacious in mouse models of ARDSthat can be advanced to additional efficacy, toxicity, and PK/PD studies in a Phase II project. The goal of thePhase II project will be to identify potent NCEs that can be moved to IND-enabling studies.Artus Therapeutics PA-20-260 / PI: Frederick M. Ausubel - Page 1 of 1
Public Health Relevance Statement: First-in-class small molecules that enhance lung barrier function during acute respiratory distress syndrome
(ARDS) as potential therapeutics for COVID-19
PA-20-260, R43 Phase I SBIR
PI: Frederick M. Ausubel
Project Narrative
An unacceptably large number of COVID-19 patients succumb to acute respiratory distress syndrome
(ARDS) caused by the break down of vascular and epithelial barriers that allow fluids to accumulate in the lung
airway. There are no therapeutics currently available for COVID-19 patients with ARDS that specifically target
barrier functions. Artus Therapeutics is developing first-in-class orally available low molecular weight compounds
that specifically enhance barrier function and are highly efficacious in mouse models of lung vascular leakage
that mimic ARDS.
Artus Therapeutics PA-20-260 / PI: Frederick M. Ausubel Project Narrative - Page 1 of 1
Project Terms: Acids ; Oral Administration ; Oral Drug Administration ; intraoral drug delivery ; Anti-Inflammatory Agents ; Anti-Inflammatories ; Anti-inflammatory ; Antiinflammatories ; Antiinflammatory Agents ; antiinflammatory ; Bifidobacterium ; Biological Assay ; Assay ; Bioassay ; Biologic Assays ; Blood Vessels ; vascular ; Bone Marrow ; Bone Marrow Reticuloendothelial System ; Blood capillaries ; capillary ; Cell Culture Techniques ; cell culture ; Cells ; Cell Body ; Ulcerative Colitis ; Ulcerated Colitis ; Dyes ; Coloring Agents ; Endothelium ; Vascular Endothelium ; Enzymes ; Enzyme Gene ; Epithelial Cells ; Evans blue stain ; Azovan Blue ; Evans Blue ; Exhibits ; Extravasation ; Leakage ; Spillage ; Goals ; Government ; Histamine ; Human ; Modern Man ; Infection ; Influenza ; Grippe ; 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 ; Lead ; Pb element ; heavy metal Pb ; heavy metal lead ; Lung ; Lung Respiratory System ; pulmonary ; macrophage ; MÏ ; Molecular Weight ; Mus ; Mice ; Mice Mammals ; Murine ; Persons ; Patients ; Permeability ; Drug Kinetics ; Pharmacokinetics ; Proteins ; Publishing ; Adult Respiratory Distress Syndrome ; ARDS ; Acute Respiratory Distress ; Acute Respiratory Distress Syndrome ; Adult ARDS ; Adult RDS ; Da Nang Lung ; Shock Lung ; Stiff lung ; wet lung ; Rodent ; Rodentia ; Rodents Mammals ; Serum Proteins ; Stomach ; gastric ; Testing ; Tissues ; Body Tissues ; transcription factor ; Basal Transcription Factor ; Basal transcription factor genes ; General Transcription Factor Gene ; General Transcription Factors ; Transcription Factor Proto-Oncogene ; Transcription factor genes ; Trinitrobenzenesulfonic Acid ; Up-Regulation ; Upregulation ; Virus Diseases ; Viral Diseases ; viral infection ; virus infection ; virus-induced disease ; Work ; Aryl Hydrocarbon Receptor ; 2,3,7,8-Tetrachlorodibenzo-p-dioxin Receptors ; AH Receptors ; Dioxin Receptors ; Nuclear Translocator ; Polyaromatic Hydrocarbon Receptors ; TCDD Receptors ; cytokine ; Sodium Dextran Sulfate ; Mediating ; base ; Phase ; Chemicals ; Epithelial ; Endothelial Cells ; alveolar epithelium ; Lung Alveolar Epithelia ; intestinal epithelium ; Tight Junctions ; Occluding Junctions ; Zonula Occludens ; analog ; 7B4 Antigen ; 7B4 protein ; CD144 Antigen ; VE-Cadherin ; Vascular Endothelial Cadherin ; Vascular Endothelial Cadherin 1 ; cadherin 5 ; Therapeutic ; fluid ; liquid ; Liquid substance ; Attenuated ; Inflammatory ; Immunes ; Immune ; Oral ; Nuclear ; interstitial ; Toxicities ; Toxic effect ; (TNF)-α ; Cachectin ; Macrophage-Derived TNF ; Monocyte-Derived TNF ; TNF ; TNF A ; TNF Alpha ; TNF-α ; TNFA ; TNFα ; Tumor Necrosis Factor ; Tumor Necrosis Factor-alpha ; TNF gene ; Lung Parenchyma ; Lung Tissue ; Structure of parenchyma of lung ; Gut Epithelium ; gastrointestinal epithelium ; Modeling ; monolayer ; Adhering Junction ; Adhesive Junction ; Anchoring Junction ; Adherens Junction ; VEGF ; VEGFs ; Vascular Endothelial Growth Factors ; small molecule ; Alveolar ; Address ; Dose ; Symptoms ; Data ; Small Business Innovation Research Grant ; SBIR ; Small Business Innovation Research ; Process ; Development ; developmental ; Influenza A Virus, H1N1 Subtype ; H1N1 ; H1N1 Virus ; novel therapeutics ; new drug treatments ; new drugs ; new therapeutics ; new therapy ; next generation therapeutics ; novel drug treatments ; novel drugs ; novel therapy ; mouse model ; murine model ; potency testing ; Pulmonary Inflammation ; Pneumonitis ; lead optimization ; gut bacteria ; bacteria in the gut ; Intestinal permeability ; Gut Epithelial Permeability ; Gut Hyperpermeability ; Gut permeability ; Intestinal Epithelial Permeability ; Intestinal Hyperpermeability ; pharmacokinetics and pharmacodynamics ; PK/PD ; COVID-19 ; COVID19 ; CV-19 ; CV19 ; corona virus disease 2019 ; coronavirus disease 2019 ; COVID-19 treatment ; COVID-19 therapy ; COVID19 therapy ; COVID19 treatment ; SARS-CoV-2 therapy ; SARS-CoV-2 treatment ; coronavirus disease 2019 therapy ; coronavirus disease 2019 treatment ; severe acute respiratory syndrome coronavirus 2 therapy ; severe acute respiratory syndrome coronavirus 2 treatment ; treat COVID-19 ; treat COVID19 ; treat SARS-CoV-2 ; treat coronavirus disease 2019 ; treat severe acute respiratory syndrome coronavirus 2 ; COVID-19 therapeutics ; COVID19 therapeutics ; SARS-CoV-2 therapeutics ; SARS-coronavirus-2 therapeutics ; Severe acute respiratory syndrome coronavirus 2 therapeutics ; coronavirus disease 2019 therapeutics ; therapeutics against COVID-19 ; therapeutics against COVID19 ; therapeutics against SARS-CoV-2 ; therapeutics against SARS-coronavirus-2 ; therapeutics against Severe acute respiratory syndrome coronavirus 2 ; therapeutics against coronavirus disease 2019 ; therapeutics for novel coronavirus ; COVID-19 patient ; COVID infected patient ; COVID patient ; COVID positive patient ; COVID-19 infected patient ; COVID-19 positive patient ; COVID19 patient ; COVID19 positive patient ; SARS-CoV-2 infected patient ; SARS-CoV-2 patient ; SARS-CoV-2 positive patient ; coronavirus disease 2019 infected patient ; coronavirus disease 2019 patient ; coronavirus disease 2019 positive patient ; coronavirus disease infected patient ; coronavirus disease patient ; coronavirus disease positive patient ; coronavirus patient ; 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 ; severe acute respiratory syndrome coronavirus 2 infected patient ; severe acute respiratory syndrome coronavirus 2 patient ; severe acute respiratory syndrome coronavirus 2 positive patient ; dietary ; SARS-CoV-2 infection ; COVID-19 infection ; COVID19 infection ; SARS-CoV2 infection ; Severe acute respiratory syndrome coronavirus 2 infection ; coronavirus disease 2019 infection ; 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 ;
