FTY720的类似物抑制TRPM7,但不抑制S1PR,并且具有多式抗炎作用
Gregory W Busey1, Mohan C Manjegowda1, Tao Huang1
1Pharmacology Department, University of Virginia School of Medicine, Charlottesville, VA, USA.
The Journal of general physiology
|November 9, 2023
概括
新型TRPM7抑制剂VPC01091.4和AAL-149在巨细胞和体内模型中显示出强大的抗炎作用. 这些化合物针对TRPM7独立于基-1-酸盐受体,为炎症性疾病提供了新的治疗途径.
科学领域:
- 免疫学 免疫学 免疫学
- 药理学 药理学是指药理学的学科.
- 细胞生物学 细胞生物学
背景情况:
- TRPM7是一种通道激酶,在巨细胞炎症激活中起着至关重要的作用.
- 选择性TRPM7抑制剂是免疫调节所需的,但现有的药物,如FTY720,具有非目标效应.
- FTY720的代谢物FTY720-酸盐激活sphingosine-1-phosphate (S1P) 受体,使其使用变得复杂.
研究的目的:
- 评估非酸化FTY720类同类作为选择性TRPM7抑制剂.
- 评估这些类似物体的体内耐受性,组织生物可用性和抗炎疗效.
- 为了研究独立于S1P受体活性的TRPM7抑制.
主要方法:
- 补丁电生理学测量TRPM7通道活动.
- 在实验室中对巨细胞进行研究,以评估炎症性细胞因子表达.
- 在体内药理动力学研究和内毒性病的小鼠模型.
主要成果:
- 在低微分子度下,VPC01091.4和AAL-149抑制了TRPM7电流.
- 这些类似物减少了巨细胞中脂多糖诱导的炎症性细胞因子表达.
- VPC01091.4显示出快速的脑和肺积累以及对微质细胞和膜巨细胞的抗炎作用.
- VPC01091.4 在小鼠内毒毒症模型中有效降低了全身炎症.
结论:
- 确定了针对TRPM7的新型小分子抑制剂.
- 这些抑制剂提供独立于S1P受体活性的TRPM7通道阻塞.
- VPC01091.4在体外和体内表现出强大的多模式抗炎活性,表明治疗潜力.
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