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

doi:10.1073/pnas.1816734116

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

Microbiology-Immunology

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43 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 language	English (US)
Pages (from-to)	6932-6937
Number of pages	6
Journal	Proceedings of the National Academy of Sciences of the United States of America
Volume	116
Issue number	14
DOIs	https://doi.org/10.1073/pnas.1816734116
State	Published - Apr 2 2019

Keywords

Glucocorticoid
High potency
Steroid-resistant asthma
VSG158
VSG159

ASJC Scopus subject areas

General

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10.1073/pnas.1816734116

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He, Y., Shi, J., Nguyen, Q. T., You, E., Liu, H., Ren, X., Wu, Z., Li, J., Qiu, W., Khoo, S. K., Yang, T., Yi, W., Sun, F., Xi, Z., Huang, X., Melcher, K., Min, B., & Eric Xu, H. (2019). Development of highly potent glucocorticoids for steroid-resistant severe asthma. Proceedings of the National Academy of Sciences of the United States of America, 116(14), 6932-6937. https://doi.org/10.1073/pnas.1816734116

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title = "Development of highly potent glucocorticoids for steroid-resistant severe asthma",

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.",

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author = "Yuanzheng He and Jingjing Shi and Nguyen, {Quang Tam} and Erli You and Hongbo Liu and Xin Ren and Zhongshan Wu and Jianshuang Li and Wenli Qiu and Khoo, {Sok Kean} and Tao Yang and Wei Yi and Feng Sun and Zhijian Xi and Xiaozhu Huang and Karsten Melcher and Booki Min and {Eric Xu}, H.",

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He, Y, Shi, J, Nguyen, QT, You, E, Liu, H, Ren, X, Wu, Z, Li, J, Qiu, W, Khoo, SK, Yang, T, Yi, W, Sun, F, Xi, Z, Huang, X, Melcher, K, Min, B & Eric Xu, H 2019, 'Development of highly potent glucocorticoids for steroid-resistant severe asthma', Proceedings of the National Academy of Sciences of the United States of America, vol. 116, no. 14, pp. 6932-6937. https://doi.org/10.1073/pnas.1816734116

TY - JOUR

T1 - Development of highly potent glucocorticoids for steroid-resistant severe asthma

AU - He, Yuanzheng

AU - Shi, Jingjing

AU - Nguyen, Quang Tam

AU - You, Erli

AU - Liu, Hongbo

AU - Ren, Xin

AU - Wu, Zhongshan

AU - Li, Jianshuang

AU - Qiu, Wenli

AU - Khoo, Sok Kean

AU - Yang, Tao

AU - Yi, Wei

AU - Sun, Feng

AU - Xi, Zhijian

AU - Huang, Xiaozhu

AU - Melcher, Karsten

AU - Min, Booki

AU - Eric Xu, H.

PY - 2019/4/2

Y1 - 2019/4/2

N2 - 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.

AB - 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.

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Development of highly potent glucocorticoids for steroid-resistant severe asthma

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