狄克托皮佩拉津/皮佩里丁类化合物作为一种潜在的宽谱冠状病毒进入抑制剂,通过超级计算机的虚拟查从一个大型的自然产品图书馆的基于虚拟查确定
Nasim Shahhamzehei1, Sara Abdelfatah1, Ejlal A Omer1
1Department of Pharmaceutical Biology, Institute of Pharmaceutical and Biomedical Sciences, Johannes Gutenberg University, Staudinger Weg 5, Mainz 55128, Germany.
Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie
|January 14, 2025
概括
一种新的天然产品化合物通过阻断尖端蛋白质,有效地抑制SARS-CoV-2和其他冠状病毒的进入.
科学领域:
- 药物的发现和开发.
- 病毒学 病毒学
- 计算化学是一种计算化学.
背景情况:
- 随着COVID-19的流行,人们越来越需要广泛的抗病毒药物来对抗冠状病毒.
- 疫苗至关重要,但防止病毒进入的抗病毒剂对于新兴变种和其他冠状病毒至关重要.
- 自然产品为开发新型抗病毒疗法提供了有希望的来源.
研究的目的:
- 为了识别抑制冠状病毒尖端蛋白受体结合域 (RBD) 功能的基于天然产品的化合物.
- 评估已识别的化合物对SARS-CoV-2和其他冠状病毒的抗病毒活性和安全性.
- 阐明潜在的泛冠状病毒进入抑制剂的作用机制.
主要方法:
- 使用Snakemake工作流程对超过21万种天然产品化合物的SARS-CoV-2,SARS-CoV和MERS-CoV RBD进行虚拟查.
- 在HEK-ACE2和Vero E6细胞中使用伪病毒和活病毒进行体外抗病毒测试.
- 细胞活力测试 (细胞毒性),微尺度热泳 (结合亲和力) 和分子对接研究.
主要成果:
- 一种N-异环化合物,一种二基托皮佩拉зин/皮佩里丁类化合物,在抗SARS-CoV-2伪病毒和活病毒入侵方面显示出低微分子IC50值.
- 该化合物在HEK-ACE2,Vero E6和MRC5细胞系中表现出低细胞毒性.
- 证实了多种冠状病毒 (SARS-CoV-2,XBB,SARS-CoV,MERS-CoV,HCoV-HKU1) 对RBD的强 binding,结合性亲和力与序列相似性相关.
结论:
- 已识别的狄基托皮佩拉津/皮佩里丁类化合物作为一种强大的泛冠状病毒进入抑制剂.
- 这种化合物显示出进一步开发的潜力,作为一种治疗剂,可以对抗一系列的冠状病毒感染.
- 用天然产品衍生化合物向RBD代表了打击当前和未来的冠状病毒威胁的可行策略.
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