Development of highly potent glucocorticoids for steroid-resistant severe asthma

• DOI: 10.1073/pnas.1816734116
• Publication Date: 2019-03-20T23:14:32Z
• Authors: Yuanzheng He; Jingjing Shi; Quang Tam Nguyen; Erli You; Hongbo Liu; Xin Ren; Zhongshan Wu; Jianshuang Li; Wenli Qiu; Sok Kean Khoo; Tao Yang; Wei Yi; Feng Sun; Zhijian Xi; Xiaozhu Huang; Karsten Melcher; Booki Min; H. Eric Xu
• Keywords: Male; 0301 basic medicine; Severity of Illness Index; steroid-resistant asthma; Mice; 03 medical and health sciences; Glucocorticoid; Receptors, Glucocorticoid; Drug Development; Receptors; Animals; Anti-Asthmatic Agents; Lung; Glucocorticoids; Animal; steroid resistant asthma; Asthma; 3. Good health; Disease Models, Animal; 5.1 Pharmaceuticals; Disease Models; Respiratory; glucocorticoid; VSG158; Female; Development of treatments and therapeutic interventions; VSG159; high potency

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.