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Development of highly potent glucocorticoids for steroid-resistant severe asthma
- Source :
- Proceedings of the National Academy of Sciences of the United States of America, vol 116, iss 14
- Publication Year :
- 2019
- Publisher :
- eScholarship, University of California, 2019.
-
Abstract
- Clinical application of inhaled glucocorticoids (GCs) has been hampered in the case of steroid-resistant severe asthma. To overcome this limitation, we have developed a series of highly potent GCs, including VSGC12, VSG158, and VSG159 based on the structural insight into the glucocorticoid receptor (GR). Particularly, VSG158 exhibits a maximal repression of lung inflammation and is 10 times more potent than the currently most potent clinical GC, Fluticasone Furoate (FF), in a murine model of asthma. More importantly, VSG158 displays a unique property to reduce neutrophilic inflammation in a steroid-resistant airway inflammation model, which is refractory to clinically available GCs, including dexamethasone and FF. VSG158 and VSG159 are able to deliver effective treatments with reduced off-target and side effects. In addition, these GCs also display pharmacokinetic properties that are suitable for the inhalation delivery method for asthma treatment. Taken together, the excellent therapeutic and side-effect profile of these highly potent GCs holds promise for treating steroid-resistant severe asthma.
- Subjects :
- Male
Animal
steroid resistant asthma
Severity of Illness Index
Asthma
Mice
steroid-resistant asthma
Glucocorticoid
Drug Development
5.1 Pharmaceuticals
Disease Models
Receptors
Respiratory
Animals
Female
VSG158
glucocorticoid
Anti-Asthmatic Agents
Development of treatments and therapeutic interventions
Glucocorticoids
Lung
VSG159
high potency
Subjects
Details
- Database :
- OpenAIRE
- Journal :
- Proceedings of the National Academy of Sciences of the United States of America, vol 116, iss 14
- Accession number :
- edsair.od.......325..d80e264de82e1d80e99fc3e3ce00f138