First-in-class small molecules that enhance lung barrier function during acute respiratory distress syndrome (ARDS) as potential therapeutics for COVID-19

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 Summary 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 capillary endothelium as well as tight junctions in the alveolar epithelium. This allows fluid, serum proteins, and immune cells to leak out of alveolar capillaries into lung interstitial tissues and then through the alveolar epithelium into the alveolar airway. There are no therapeutics approved for ARDS that directly target tight and adherens junctions, even though accumulating evidence suggests that therapeutics that shore up these junctions could be highly efficacious for ARDS patients. To address this unmet need, Artus Therapeutics is developing novel therapeutics that directly enhance both epithelial and endothelial barrier function in the lungs. Artus's lead compound, ARTX-2, is a low molecular weight orally available molecule inspired by the natural gut metabolite Urolithin A. Oral administration of ARTX-2 decreases vascular leakage into lung tissue in mice treated with LPS to 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-elicited permeability. With respect to epithelial barrier function, ARTX-2 up-regulates several tight junction proteins and decreases permeability of intestinal epithelial cells. Oral administration of ARTX-2 dramatically mitigates symptoms in mouse models of ulcerative colitis by restoring gut epithelial barrier function. Further, ARTX-2 blocks 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 the treatment of COVID-19 patients because it may enhance both lung endothelial and lung epithelial barrier function and decrease the levels of inflammatory cytokines without being immunosuppressive. In addition to the lead compound ARTX-2, 44 ARTX-2 analogs have been synthesized for lead optimization studies. Two specific aims test 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-2 analogs will be more potent than ARTX-2. In Aim 1, we propose to test the potency of 44 ARTX-2 analogs in comparison to ARTX-2 in upregulating the expression of tight junction proteins and VE-cadherin in lung epithelial and lung endothelial cell cultures. The 5 most potent analogs will be prioritized for further study in Aim 2. In Aim 2, 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 result in the identification of 2-3 new chemical entities (NCEs) that are highly efficacious in mouse models of ARDS that can be advanced to additional efficacy, toxicity, and PK/PD studies in a Phase II project. The goal of the Phase 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 Project Summary - Page 1 of 1