体聚合混了基于细胞的Covid-19抗病毒查
Isabella S Glenn1, Lauren N Hall1, Mir M Khalid2,3
1Department of Pharmaceutical Chemistry, University of California San Francisco (UCSF), San Francisco, CA, USA.
bioRxiv : the preprint server for biology
|November 14, 2023
概括
候选药物中的体聚合可以在COVID-19抗病毒查中引起假阳性. 用BSA或洗剂进行预和可以通过破坏这些聚合物来揭示真正的药物疗效.
科学领域:
- 药物发现和化学生物学
- 病毒学和传染病学.
- 生物物理学和合物科学
背景情况:
- 体聚合是早期药物发现中错误阳性结果的重要来源.
- 它对针对COVID-19药物重新定位的基于细胞的感染性测试的影响仍未得到充分研究.
- 了解聚合对于准确评估抗病毒化合物至关重要.
研究的目的:
- 调查SARS-CoV-2进入抑制剂候选物中体聚合的作用.
- 评估聚合对基于细胞的试验中的抗病毒疗效的影响.
- 在药物查中开发反幕,以识别和消除聚合工件.
主要方法:
- 动态光散射用于检测环状颗粒的形成.
- 有或没有洗剂的酶抑制测定.
- 用牛血清白蛋白 (BSA) 预和进行的Spike伪型的lentivirus感染性测定.
- 同焦显微镜可视化蛋白质聚合物相互作用.
主要成果:
- 在41种候选药物中,17种药物形成了体颗粒,并表现出对洗剂的依赖性抑制.
- BSA 预和降低或消除了聚合化合物的明显抗病毒功效 (≥10倍).
- 聚焦显微镜证实了尖端蛋白质被聚合物绑定,被BSA或洗剂破坏.
结论:
- 体聚合是基于细胞的抗病毒药物对COVID-19进行重新定位的常见工件.
- 聚合可以掩盖真正的化合物疗效,导致假阳性.
- 使用BSA或洗剂的快速反可以识别和减轻这些文物,提高药物发现效率.
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