在刺功能测定中识别具有活性的声波刺/肝素结合的小分子对抗剂
David R Lamson1, Michael Tarpley1, Kezia Addo1
1Biomanufacturing Research Institute and Technology Enterprise, USA.
Biochimica et biophysica acta. General subjects
|August 16, 2024
概括
研究人员选了34560种化学物质,以寻找阻断Sonic hedgehog (Shh) 与肝素结合的小分子. 他们发现了抑制SHH信号的新型抗体,为癌症研究提供了潜在的工具.
科学领域:
- 生物化学 生化学
- 分子生物学分子生物学
- 药物发现 药物发现 药物发现
背景情况:
- 声波刺 (Shh) 是胚胎发育和癌症的关键形态原体.
- SHH活性通过与肝素和肝素硫酸蛋白质糖 (HSPG) 的相互作用来调节.
研究的目的:
- 为了识别Shh / 肝素结合的新型小分子对手.
- 研究那些抑制SHH信号通路的化合物.
主要方法:
- 对34560种化学物质进行了SHH/肝素结合抗剂的选.
- 在体外测试测量性酸酶活性和Gli1 mRNA诱导.
- 热转移测试和分子对接以确认化合物结合.
主要成果:
- 确定了26种新的小分子对抗剂.
- 十九种化合物抑制了ShhN与肝素的结合 (IC50 < 50μM).
- 两个化合物表明选择性抑制ShhN介导的信号传递和直接结合ShhN.
结论:
- 阻断ShhN-氨酸相互作用的小分子可以抑制Shh信号传递.
- Shh-HSPG相互作用是开发Shh对手的可行目标.
- 已识别的化合物可以作为研究SHH功能的潜在工具.
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