Discovery of a highly potent glucocorticoid for asthma treatment.
Discovery of a highly potent glucocorticoid for asthma treatment.
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发现用于治疗哮喘的高效糖皮质激素
DOI：
10.1038/celldisc.2015.35
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发表时间：
2015
期刊：
影响因子：
33.5
通讯作者：
Xu HE
中科院分区：
文献类型：
--
作者：
He Y;Shi J;Yi W;Ren X;Gao X;Li J;Wu N;Weaver K;Xie Q;Khoo SK;Yang T;Huang X;Melcher K;Xu HE
糖皮质激素是治疗哮喘最有效的药物。然而，它们的临床应用受到严重哮喘的低功效以及与高剂量或长期使用相关的不期望的副作用的限制。克服这些局限性的最成功的方法是开发高效糖皮质激素，其可以通过吸入递送到肺部以实现局部功效，同时具有最小的全身效应。在我们以前的结构研究的基础上，我们设计并开发了一种高效的糖皮质激素，VSGC12，它在基于细胞的报告基因测定和细胞因子抑制实验以及小鼠巨噬细胞RAW 264的基因表达谱中显示出改善的抗炎活性。7个细胞。在小鼠哮喘模型中，VSGC12在包括组织学和分化免疫细胞数量在内的许多类别中提供了比糠酸氟替卡松更高的疗效。VSGC12在抑制大多数哮喘症状方面也显示出比糠酸氟替卡松更高的效力。最后，VSGC12在其各自的有效剂量下显示出比糠酸氟替卡松更好的副作用特征，包括在动物模型中更好的胰岛素反应和更少的骨丢失。VSGC12的优良的治疗和副作用特性为开发这种强效糖皮质激素作为治疗哮喘的新药物提供了有希望的前景。
Glucocorticoids are the most effective treatment for asthma. However, their clinical applications are limited by low efficacy in severe asthma and by undesired side effects associated with high dose or prolonged use. The most successful approach to overcome these limitations has been the development of highly potent glucocorticoids that can be delivered to the lungs by inhalation to achieve local efficacy with minimal systemic effects. On the basis of our previous structural studies, we designed and developed a highly potent glucocorticoid, VSGC12, which showed an improved anti-inflammation activity in both cell-based reporter assays and cytokine inhibition experiments, as well as in a gene expression profiling of mouse macrophage RAW264. 7 cells. In a mouse asthma model, VSGC12 delivered a higher efficacy than fluticasone furoate, a leading clinical compound, in many categories including histology and the number of differentiated immune cells. VSGC12 also showed a higher potency than fluticasone furoate in repressing most asthma symptoms. Finally, VSGC12 showed a better side effect profile than fluticasone furoate at their respective effective doses, including better insulin response and less bone loss in an animal model. The excellent therapeutic and side effect properties of VSGC12 provide a promising perspective for developing this potent glucocorticoid as a new effective drug for asthma.