ELD607, inhaled Orai1 Antagonist
Lung inflammation is a common phenotype of many lung diseases, including but not limited to asthma, acute respiratory distress syndrome (ARDS), cystic fibrosis (CF), chronic obstructive pulmonary disease (COPD), and viral lung infections. For many of these diseases, inflammation is poorly controlled.
- 3 million people in the USA have steroid-resistant asthma.
- Ibuprofen is the only anti-inflammatory therapy approved for CF, but it can cause adverse effects, including gastrointestinal bleeding.
- ARDS is characterized by excessive neutrophilic inflammation but has no treatment and a 30% mortality rate.
ELD607 is a fully optimized Orai1-specific antagonist that is designed to reduce lung inflammation. ELD607 is a first-in-class molecule that is differentiated from existing Orai1 antagonists due to its novel mechanism of action. ELD607 binds extracellularly to Orai1, leading to internalization and degradation of the channel. ELD607 also has a long duration of action, and its effects persist even after drug washout.
A surprising benefit of ELD607-mediated reductions in neutrophilia is that ELD607 encourages alveolar macrophage-dependent clearance of bacteria from the lung. Indeed, we consistently observe 10,000- to 100,000-fold CFU reductions in both Gram-positive and Gram-negative bacteria, including MRSA from mouse lungs. Thus, by retraining the lung’s immune system, ELD607 has the potential to treat hard-to-treat antibiotic-resistant bacteria.
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YFP-Orai1 (green) exposed to saline with ELD607
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YFP-Orai1 was expressed in HEK293T cells for 24 h. Cells were exposed to saline or saline with ELD607 for 45 minutes, and image stacks were obtained by confocal microscopy. Stacks were then rendered in three dimensions.