发现了EGT710,一种口服非皮多米米特反转共价性SARS-CoV-2主要蛋白酶抑制剂
Julien P N Papillon1, Jun Yuan1, Matthew J Hesse2
1Global Discovery Chemistry, Biomedical Research, Novartis, Cambridge, Massachusetts 02139, United States.
Journal of medicinal chemistry
|February 9, 2026
概括
研究人员发现了EGT710,这是一种针对冠状病毒主要蛋白酶 (Mpro) 的新型非胺抑制剂. 这种化合物对SARS-CoV-2具有强烈的活性,支持其进入COVID-19治疗临床研究的进展.
科学领域:
- 药用化学 医学化学
- 病毒学 病毒学
- 结构生物学 结构生物学
背景情况:
- 新冠病毒主要蛋白酶 (3CL,M) 是病毒复制周期中的关键酶,也是COVID-19的验证治疗点.
- 与传统的类药物相比,非类药物抑制剂有可能改善药理学概况.
- SARS-CoV-2 Mpro对病毒多蛋白质加工至关重要,是抗病毒药物开发的关键目标.
研究的目的:
- 鉴定新型的,非胺胺基的冠状病毒主要蛋白酶 (Mpro) 抑制剂,具有潜在的优异药物类特性.
- 利用基于结构的药物设计,虚拟查和X射线晶体学来发现强大的Mpro抑制剂.
- 优化化合物以增强药理动力学特性,可开发性和对各种冠状病毒的广泛活性.
主要方法:
- 基于结构的药物设计,利用Mpro.的X射线结晶学数据.
- 虚拟选用于识别最初的打击化合物.
- 优化侧重于药物化学修改,以改善功效和药物动力学参数.
- 在体外细胞测试中,使用差异化正常的人类支气管上皮细胞 (dNHBE) 来评估针对SARS-CoV-2的抗病毒活性.
主要成果:
- 发现了一系列新的quinazoline-2,4(1H,3H) -dione和oxoimidazolidine-4-carbonitrile化合物,这些化合物表现出强大的SARS-CoV-2 Mpro的抑制作用.
- 鉴定EGT710作为在dNHBE细胞中对SARS-CoV-2感染具有优异功效的主要候选物.
- EGT710表现出有利的药理学特征,支持其进入临床前和临床开发的进展.
结论:
- 使用基于结构的药物设计,可以有效地发现和开发针对冠状病毒Mpro的非胺基因抑制剂.
- EGT710代表了治疗COVID-19和潜在的其他冠状病毒感染的有希望的治疗候选者.
- 已识别的化合物系列和优化策略为开发下一代抗冠病毒药物的基础.
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