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作为SARS-CoV-2的主要蛋白酶抑制剂,具有独特的共价核弹头的阿扎

Kaustav Khatua¹, Yugendar R Alugubelli¹, Kai S Yang¹

¹Texas A&M Drug Discovery Center and Department of Chemistry, Texas A&M University, College Station, TX 77854, USA.

Antiviral research

|March 30, 2024

概括

研究人员开发了针对SARS-CoV-2主要蛋白酶 (M^Pro) 的新型阿扎胺抑制剂,这对病毒复制至关重要. 强效抑制剂MPI89对COVID-19治疗开发有显著的前景.

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:

SARS-CoV-2 主蛋白酶 (M^Pro) 对于病毒复制和病变产生至关重要.
M^Pro 具有活跃部位口袋和一种对其酶功能至关重要的催化氨酸.

研究的目的:

为了合成和描述针对SARS-CoV-2 M^Pro的新型阿扎类抑制剂.
为了确定潜在的COVID-19抗病毒疗法的强效和选择性抑制剂.

主要方法:

用共价核弹头合成各种阿扎胺抑制剂.
生物化学和细胞测试以确定抑制剂的强度 (EC₅₀) 和选择性.
进行X射线晶体学以阐明抑制剂-M^Pro的结合相互作用.

主要成果:

在ACE2+A549细胞中识别强大的M^Pro抑制剂,包括具有10nM的EC₅₀的MPI89对SARS-CoV-2的EC₅₀.
MPI89表现出高选择性指数 (875) 和对SARS-CoV-2帕帕因类蛋白酶和人类蛋白酶的选择性.
结晶学证实了催化氨酸的共价结合和由抑制剂与氧化离子孔的结合.

结论:

阿扎,特别是那些具有像MPI89这样的aza-2,2-dichloroacetyl弹头的阿扎,是非常有效的M^Pro抑制剂.
MPI89代表了一种有前途的化合物,用于开发针对COVID-19的新疗法.
对阿扎胺抑制剂的进一步探索需要对抗病毒药物发现进行调查.

关键词:

亚扎胺是一种阿扎胺.在 COVID-19 疫情中,协同抑制剂协同抑制剂主要蛋白质酶的主要蛋白质酶.这就是SARS-CoV-2病毒.

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