向甲素的SARS-CoV-2抑制剂:设计,合成和生物活动
Philipp Flury1, Julian Breidenbach2, Nadine Krüger3
1Institute of Pharmacy, Pharmaceutical/Medicinal Chemistry and Tübingen Center for Academic Drug Discovery, Eberhard Karls University Tübingen, Auf der Morgenstelle 8, Tübingen 72076, Germany.
ACS pharmacology & translational science
|February 15, 2024
概括
新的类仿制药在抑制甲素 (Cats) 和SARS-CoV-2的进入方面表现有前途. 化合物11e表现出强大的抗病毒活性和有利于进一步发展的特性.
科学领域:
- 生物化学 生物化学
- 病毒学 病毒学
- 药用化学 医学化学
背景情况:
- 甲素 (Cats) 是对SARS-CoV-2宿主细胞进入至关重要的蛋白质酶.
- 抑制这些蛋白酶是对抗病毒感染的治疗策略.
研究的目的:
- 设计和合成针对人体甲素L,B和S的新型型模仿药物.
- 评估这些化合物对SARS-CoV-2的抑制和抗病毒活性.
主要方法:
- 合成21种具有各种弹头功能和封闭组的类模拟剂.
- 在实验室中评估了对Cathepsin L,B,S和SARS-CoV-2主要蛋白酶 (Mpro) 的抑制活性.
- 基于细胞的抗病毒测定和细胞毒性评估.
主要成果:
- 几种化合物表现出对Cathepsin L和S的强烈抑制,K_i值在纳米分子到亚纳米分子范围内.
- 酸11e在Calu-3细胞中显示出显著的抗病毒活性 (EC50 = 38.4nM),没有细胞毒性.
- 化合物11e表现出高的代谢稳定性和有利的药理动力学特性.
结论:
- 开发的类仿制药是甲素和SARS-CoV-2的有效抑制剂.
- 化合物11e是作为抗病毒剂进一步临床前开发的有希望的候选物.
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