Specific Inhibition of Orai1-mediated Calcium Signalling Resolves Inflammation and Clears Bacteria in an Acute Respiratory Distress Syndrome Model

• Published in: American journal of respiratory and critical care medicine Vol. 209; no. 6; pp. 703 - 715
• Main Authors: Ahmad, Saira, Wrennall, Joe A., Goriounova, Alexandra S., Sekhri, Malika, Iskarpatyoti, Jason A., Ghosh, Arunava, Abdelwahab, Sabri H., Voeller, Alexis, Rai, Mani, Mahida, Rahul Y., Krajewski, Krzysztof, Ignar, Diane M., Greenbaum, Alon, Moran, Timothy P., Tilley, Stephen L., Thickett, David R., Sassano, M. Flori, Tarran, Robert
• Format: Journal Article
• Language: English
• Published: New York American Thoracic Society 15.03.2024
• Subjects: Antagonist drugs; Bacterial infections; Drug therapy; Inflammation; Pneumonia; Respiratory distress syndrome
• ISSN: 1073-449X; 1535-4970; 1535-4970
• DOI: 10.1164/rccm.202308-1393OC

ELD607 is a novel Orai1 antagonist that shows promise in treating acute respiratory distress syndrome (ARDS) caused by bacterial pneumonia. ARDS has a high mortality rate and currently lacks effective therapy. Orai1 is a calcium channel involved in inflammation regulation, and ELD607 specifically inhibits Orai1-mediated calcium signaling. In preclinical models, ELD607 reduced neutrophilia, improved survival, and promoted macrophage-mediated resolution of inflammation and clearance of bacteria. The peptide was stable in ARDS airway secretions and showed efficacy in inhibiting Orai1 in immune cells from ARDS patients. ELD607 also normalized BAL leukocytes, reduced proinflammatory cytokines, and improved lung histology and oxygen saturation. The peptide targeted macrophages to reduce inflammation and bacterial burden. ELD607 represents a novel approach to reduce multi-organ inflammation and treat antibiotic-resistant bacteria in ARDS. Further studies are needed to advance ELD607 into human clinical trials.