发现ICOS向的小分子使用亲和力选择质谱检测选ICOS的发现
Longfei Zhang1, Laura Calvo-Barreiro1, Victor de Sousa Batista2
1Department of Radiology, Molecular Imaging Innovations Institute (MI3), Weill Cornell Medicine, New York, NY 10065, USA.
bioRxiv : the preprint server for biology
|August 16, 2024
概括
研究人员发现了向诱导性T细胞共刺激器 (ICOS) 途径的小分子,这是一个关键的免疫检查点. 这项工作为癌症和自身免疫性疾病的新型小分子疗法提供了潜力.
科学领域:
- 免疫学 免疫学 免疫学
- 药用化学 医学化学
- 生物化学 生物化学
背景情况:
- 诱导性T细胞共刺激器 (ICOS) 是激活的T细胞上的积极免疫检查点受体.
- 在癌症和自身免疫性疾病中,ICOS调制显示出临床益处.
- 目前的ICOS调节器是生物制剂,因此需要小分子替代品.
研究的目的:
- 为了发现针对ICOS路径的新型小分子.
- 确定一种用于开发小分子ICOS调节器的化合物.
主要方法:
- 对15600个分子进行ICOS结合的亲和选择质谱 (ASMS) 选.
- 结构与活动关系 (SAR) 研究.
- 分子动力学 (MD) 模拟.
主要成果:
- 已识别的化合物9具有ICOS/ICOS-L抑制特征 (IC50 = 29.38 ± 3.41 μM).
- ASMS查成功识别了针对免疫检查点的小分子.
- MD模拟揭示了在化合物9中的正氧基团在ICOS通过键形成的结合中起着关键作用.
结论:
- 这项研究证实了ICOS/ICOS-L相互作用的有希望的小分子抑制剂.
- 这些发现为开发ICOS的强大小分子调节器铺平了道路.
- 这项研究确立了ASMS作为发现小分子免疫检查点抑制剂的可行方法.
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