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天津快乐十分快五复式:Development of highly potent glucocorticoids for steroid-resistant severe asthma
广东快乐十分投注下载 www.hmclip.net Edited by John A. Cidlowski, National Institutes of Environmental Health Sciences, Research Triangle Park, NC, and accepted by Editorial Board Member Ruslan Medzhitov February 22, 2019 (received for review September 28, 2018)
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Severe asthma generally responds poorly to traditional steroid treatment and causes most of the disability and mortality among all asthma patients. Currently, there is almost no effective treatment to control the symptoms of severe asthma. Our insight into the structure of glucocorticoid (GC) potency has enabled us to develop GCs with maximal potency to repress lung inflammation in a murine model of asthma, outperforming the currently most effective clinical compound, and is capable of delivering a treatment with reduced off-target and side effects in many categories. Most importantly, the extremely potent GC VSG158 alleviates the inflammation response in a murine steroid-resistant airway inflammation model when leading clinical compounds fail, suggesting a therapeutic potential of these GCs for controlling severe asthma.
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.
?1Y.H., J.S., and Q.T.N. contributed equally to this work.
- ?2To whom correspondence may be addressed. Email: , , , or .
?3Deceased December 18, 2017.
Author contributions: Y.H., T.Y., W.Y., X.H., K.M., B.M., and H.E.X. designed research; Y.H., J.S., Q.T.N., E.Y., H.L., X.R., Z.W., J.L., W.Q., and F.S. performed research; S.K.K. and Z.X. contributed new reagents/analytic tools; Y.H., B.M., and H.E.X. analyzed data; and Y.H. B.M., and H.E.X. wrote the paper.
Conflict of interest statement: F.S., Z.W., and Z.X. are employees and H.E.X. is a consultant of Palo Alto Pharmaceutics Inc.
This article is a PNAS Direct Submission. J.A.C. is a guest editor invited by the Editorial Board.
Data deposition: The data reported in this article have been deposited in the National Center for Biotechnology Information Gene Expression Omnibus database (accession no. GSE119789).
This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1816734116/-/DCSupplemental.
Published under the PNAS license.