Drug Repurposing to Treat Glucocorticoid Resistance in Asthma.
Drug Repurposing to Treat Glucocorticoid Resistance in Asthma.
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DOI：
10.3390/jpm11030175
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发表时间：
2021-03-03
影响因子：
--
通讯作者：
Tantisira KG
中科院分区：
文献类型：
--
作者：
Wang AL;Panganiban R;Qiu W;Kho AT;Chupp G;Meyers DA;Bleecker ER;Weiss ST;Lu Q;Tantisira KG
皮质类固醇抵抗会导致哮喘显着发病，重新调整药物用途可以找到及时且经济有效的皮质类固醇抵抗辅助治疗方法。在儿童哮喘管理计划 (CAMP) 的 95 名受试者和严重哮喘研究计划 (SARP) 的 19 名受试者中，通过预测一秒用力呼气量百分比 (FEV1) 的变化来测量皮质类固醇反应。在每个队列中，进行差异基因表达分析，将不良（耐药）反应者（定义为 FEV1 零至负变化的人）与良好反应者进行比较，然后进行连接图（CMap）分析，以识别逆相关（即负相关）药物，这些药物将不良反应者的基因表达谱逆转为与良好反应者相似。计算了按样本大小加权的平均连通性分数。排名前五的候选药物化合物在 IL-1β ± 地塞米松刺激的基于 NF-κB 的荧光素酶报告基因 A549 细胞中进行了体外验证。在 CAMP 和 SARP 中，134 个和 178 个基因在不良反应者中分别有差异表达。 CMap 分析确定了两个队列中共有 46 种化合物，其连通性得分 < -50。选择γ-亚麻酸、氨苄青霉素、依西美坦、布林佐胺和INCA-6进行功能验证。 γ-亚麻酸、布林佐胺和 INCA-6 显着降低 IL-1β 诱导的荧光素酶活性，并增强 A549/NF-κB-luc 报告细胞中地塞米松的抗炎作用。这些结果证明了如何重新利用现有药物（包括 γ-亚麻酸、布林佐胺和 INCA-6）来改善哮喘患者的皮质类固醇反应。
Corticosteroid resistance causes significant morbidity in asthma, and drug repurposing may identify timely and cost-effective adjunctive treatments for corticosteroid resistance. In 95 subjects from the Childhood Asthma Management Program (CAMP) and 19 subjects from the Severe Asthma Research Program (SARP), corticosteroid response was measured by the change in percent predicted forced expiratory volume in one second (FEV1). In each cohort, differential gene expression analysis was performed comparing poor (resistant) responders, defined as those with zero to negative change in FEV1, to good responders, followed by Connectivity Map (CMap) analysis to identify inversely associated (i.e., negatively connected) drugs that reversed the gene expression profile of poor responders to resemble that of good responders. Mean connectivity scores weighted by sample size were calculated. The top five drug compound candidates underwent in vitro validation in NF-κB-based luciferase reporter A549 cells stimulated by IL-1β ± dexamethasone. In CAMP and SARP, 134 and 178 respective genes were differentially expressed in poor responders. CMap analysis identified 46 compounds in common across both cohorts with connectivity scores < −50. γ-linolenic acid, ampicillin, exemestane, brinzolamide, and INCA-6 were selected for functional validation. γ-linolenic acid, brinzolamide, and INCA-6 significantly reduced IL-1β induced luciferase activity and potentiated the anti-inflammatory effect of dexamethasone in A549/NF-κB-luc reporter cells. These results demonstrate how existing drugs, including γ-linolenic acid, brinzolamide, and INCA-6, may be repurposed to improve corticosteroid response in asthmatics.
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