Novel Pharmacological Approach to Treat Acute Lung Injury

Abstract

Acute Respiratory Distress Syndrome (ARDS) is a lung disease characterized by acute respiratory failure, morbidity, and mortality. There are no effective therapies for ARDS, and standard care remains largely supportive. Here, we offer a novel pharmacological approach to treat ARDS by inhibiting microtubule accessory factor end binding protein 3 (EB3), which contribute to vascular leakage by amplifying pathological calcium signaling in endothelial cells. We employed structure‐activity‐relationship studies by nuclear magnetic resonance to design an allosteric inhibitor of EB3 that has optimal physicochemical and biochemical properties and is suitable for future clinical applications. Using standard methods for backbone rigidification and non‐proteinogenic amino acids, we have designed and tested sixty‐one drug‐like compounds, twenty‐six of which demonstrate remarkable similarity in binding the C‐terminus of EB3. Further screens using a cell‐based system identified four compounds with cell‐penetrating properties. These compounds are potent in inhibiting agonist‐evoked calcium release from endoplasmic reticulum stores and mitigating the effect of pro‐inflammatory mediators on the endothelial barrier. Based on in vitro stability in human blood plasma, we selected one lead and two backup compounds for further in vivo pre‐clinical studies. All three compounds inhibit endothelial capillary leakage in mice challenged with IV administration of PAR‐1 agonist peptide. Our studies establish a workflow for rational drug design to allosterically modulate EB3 function. Novel drug‐like compounds are stable and efficacious in treating lung endothelial microvascular hyperpermeability and may provide an important future clinical use in treating pulmonary edema associated with ARDS.Support or Funding InformationThis project has been funded in whole with Federal funds from the National Heart, Lung and Blood Institute, National Institutes of Health, Department of Health and Human Services, under Contract No. HHSN268201700007C to YAK.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.