开发高效糖皮质激素治疗类固醇抵抗性严重哮喘。
Development of highly potent glucocorticoids for steroid-resistant severe asthma.
机构信息
Laboratory of Receptor Structure and Signaling, HIT Center for Life Science, Harbin Institute of Technology, Harbin 150001, China;
Laboratory of Structural Sciences, Van Andel Research Institute, Grand Rapids, MI 49503.
出版信息
Proc Natl Acad Sci U S A. 2019 Apr 2;116(14):6932-6937. doi: 10.1073/pnas.1816734116. Epub 2019 Mar 20.
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.
吸入性糖皮质激素（GCs）在治疗类固醇抵抗性严重哮喘方面的临床应用受到限制。为了克服这一限制，我们基于对糖皮质激素受体（GR）的结构深入了解，开发了一系列高效的 GCs，包括 VSGC12、VSG158 和 VSG159。特别是，VSG158 在哮喘的小鼠模型中表现出最大程度的抑制肺部炎症的作用，其效力比目前最有效的临床 GC，糠酸氟替卡松（FF）强 10 倍。更重要的是，VSG158 具有独特的性质，可以减轻对临床上可用的 GCs（包括地塞米松和 FF）抵抗的类固醇抵抗性气道炎症模型中的中性粒细胞炎症。VSG158 和 VSG159 能够以减少脱靶和副作用的方式提供有效的治疗。此外，这些 GCs 还显示出适合哮喘治疗吸入递送方法的药代动力学特性。综上所述，这些高效 GCs 的出色治疗效果和副作用特征为治疗类固醇抵抗性严重哮喘提供了希望。
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