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使用TRIC技术的TREM2成功发现:一种概念验证的高通量选方法
bioRxiv : the preprint server for biology
|June 12, 2025
概括
研究人员开发了一种高通量选平台,以发现Triggering Receptor Expressed on Myeloid cells 2 (TREM2) 的小分子结合剂,克服了神经退行性疾病和癌症抗体治疗的局限性.
科学领域:
- 生物化学 生物化学
- 免疫学 免疫学 免疫学
- 药理学 药理学是指药理学的学科.
背景情况:
- 在骨髓细胞表达的触发受体2 (TREM2) 是一个关键的免疫调节受体.
- TREM2在神经退行性疾病和癌症中起作用.
- 目前的TREM2疗法,主要是单克隆抗体 (mAbs),具有诸如组织透能力差等局限性.
研究的目的:
- 开发一个高通量选 (HTS) 平台,用于识别新的小分子TREM2结合剂.
- 扩大TREM2向剂的化学空间,超出mAbs.
- 建立一种可扩展的方法来发现小分子TREM2调节器.
主要方法:
- 在NanoTemper Dianthus平台上使用了与温度相关的强度变化 (TRIC) 技术.
- 从专注的图书馆选了1200多个化合物.
- 使用微尺度热泳 (MST) 和表面等离子体共振 (SPR) 验证的命中.
- 在HEK293细胞中通过TREM2-介导的Syk酸化评估功能活性.
主要成果:
- 识别了18个初步命中 (1.44%的命中率) 来自HTS.
- 验证了四个具有高至中微分子亲和度的小分子TREM2结合剂 (例如,T2337,KD = 22.4 μM).
- 使用SPR.37确认了顶部命中 (T2337) 的结合.
- 在细胞试验中证明了验证的匹配结果的功能活性.
结论:
- 建立了一个强大的和可扩展的HTS平台,用于小分子TREM2发现.
- 提供了使用HTS识别新型TREM2调制器的概念验证.
- 为开发针对TREM2的新治疗策略铺平了道路.
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