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针对SARS-CoV-2 E蛋白与ZO-1 PDZ2相互作用的小分子的基于HTRF的识别

Flavio Alvarez^1,2, Florence Larrous³, Ariel Mechaly⁴

¹Signaling and Receptors Dynamics Unit, Institut Pasteur, Université Paris Cité, F-75015, Paris, France. a.flavio2cg@gmail.com.

Scientific reports

|December 28, 2025

概括

研究人员确定了阻断SARS-CoV-2 E蛋白的化合物.

科学领域:

病毒学病毒学
结构生物学结构生物学
药物发现药物发现药物发现

背景情况:

SARS-CoV-2 E 蛋白与 ZO-1 等宿主蛋白相互作用,有助于病毒病原.
针对E蛋白的PDZ结合动机 (PBM) 相互作用是一种潜在的治疗策略.

研究的目的:

阐明E蛋白 PBM和ZO-1 PDZ2相互作用的结构基础.
为了识别抑制这种相互作用的小分子,用于抗病毒的发展.

主要方法:

进行X射线晶体学以确定复杂的结构.
复合物库的同质时间解析光 (HTRF) 选.
细胞毒性测定,剂量反应研究,对接模拟和抗病毒测定.

主要成果:

X射线结构揭示了ZO-1 PDZ2的域互换二分体,由E PBM结合.
在HTRF查中,发现了36种抑制相互作用的化合物,其中14种在进一步测定后显示出有前途.
化合物通过竞争性结合或通过防止ZO-1二元化来抑制相互作用.
一种化合物C19在抗病毒试验中显著降低了SARS-CoV-2的复制.

结论:

通过直接或间接的机制,SARS-CoV-2 E蛋白/ZO-1 PDZ2相互作用可以被小分子抑制.
化合物C19显示出作为针对这种相互作用的抗病毒治疗候选药物的潜力.

关键词:

抗病毒化合物查对抗病毒化合物查蛋白质 E 蛋白质 E 是一种蛋白质.PDZ-绑定图案的动图是 PDZ 的绑定图案.蛋白质蛋白质相互作用这就是SARS-CoV-2病毒.ZO-1 是一个ZO-1

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Protein-protein Interfaces

Protein-protein Interfaces

Many proteins form complexes to carry out their functions, making protein-protein interactions (PPIs) essential for an organism's survival. Most PPIs are stabilized by numerous weak noncovalent chemical forces. The physical shape of the interfaces determines the way two proteins interact. Many globular proteins have closely-matching shapes on their surfaces, which form a large number of weak bonds. Additionally, many PPIs occur between two helices or between a surface cleft and a...