Development of highly potent glucocorticoids for steroid-resistant severe asthma

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

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

12 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)6932-6937
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume116
Issue number14
DOIs
StatePublished - Apr 2 2019
Externally publishedYes

Keywords

  • Glucocorticoid
  • High potency
  • Steroid-resistant asthma
  • VSG158
  • VSG159

ASJC Scopus subject areas

  • General

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