基于结构设计的共价SARS-CoV-2帕帕因类蛋白酶抑制剂
Bin Tan1, Xueying Liang2, Ahmadullah Ansari3,4
1Department of Medicinal Chemistry, Ernest Mario School of Pharmacy, Rutgers, the State University of New Jersey, Piscataway, New Jersey 08854, United States.
Journal of medicinal chemistry
|November 5, 2024
概括
针对SARS-CoV-2帕帕因类蛋白酶 (PLpro) 的新型共价抑制剂显示出强大的抗病毒活性. 这些化合物显示出对抗不断演变的病毒有前途的药物潜力,包括有利的体内特性.
科学领域:
- 病毒学 病毒学
- 药物发现 药物发现 药物发现
- 生物化学 生物化学
背景情况:
- 严重急性呼吸系统综合征-冠状病毒2 (SARS-CoV-2) 是一种正在演变的RNA贝塔冠状病毒,负责COVID-19大流行.
- SARS-CoV-2 编码的是一种类似帕帕因的蛋白酶 (PLpro),这是病毒复制和病变发生的关键酶.
- 此外,PLpro还向宿主蛋白质,包括乌比奎和ISG15,影响宿主免疫反应.
研究的目的:
- 设计和合成针对SARS-CoV-2 PLpro.的新型共价抑制剂.
- 评估设计化合物的酶抑制和抗病毒活性.
- 评估体内药理动力学特性和抑制的结构基础.
主要方法:
- 基于结构的药物设计利用了PLpro.pro的Val70Ub结合部位.
- 通过将氨酸反应性弹头与二甲基架连接在一起,合成共价抑制剂.
- 酶抑制试验 (IC50) 和基于细胞的抗病毒试验 (EC50).
- 在体内药理动力学研究和X射线结晶学.
主要成果:
- 几种设计的共价PLpro抑制剂显示出强大的酶抑制 (IC50 = 0.10.3 μM) 和抗病毒活性 (EC50 = 0.090.96 μM).
- 富马拉胺抑制剂Jun13567,Jun13728和Jun13714在体内表现出有利的药理动力学特征.
- X射线晶体学证实了抑制剂Jun13567和PLpro.的催化Cys111残留物之间的共价链接.
结论:
- 开发的共价PLpro抑制剂代表了针对SARS-CoV-2的有前途的新类抗病毒药物候选者.
- 针对Val70Ub结合部位的设计策略通过结构和功能数据进行验证.
- 这些抑制剂提供了一种潜在的治疗途径,以对抗正在进行的COVID-19大流行和未来的冠状病毒威胁.
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