一种组合和计算的Tandem方法,以实现对抗ACE2-介导的冠状病毒感染的通用治疗方法
Chia Yin Lee1, Ching-Wen Huang1, Louis De Falco2
1Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A∗STAR), 8A Biomedical Grove, Immunos #03-06, Singapore 138648, Republic of Singapore.
iScience
|June 16, 2025
概括
研究人员设计了ACE2-YHA,一种高亲和度诱受体,用于对抗像SARS-CoV-2这样的冠状病毒. 这种创新方法显示了预防和治疗各种冠状病毒感染的潜力,包括新变种.
科学领域:
- 病毒学 病毒学
- 结构生物学 结构生物学
- 蛋白质工程是指蛋白质工程.
背景情况:
- ангиотензин转化酶2 (ACE2) 受体对于冠状病毒,包括SARS-CoV和SARS-CoV-2进入宿主细胞至关重要.
- 开发针对广泛的冠状病毒的有效对策对于公共卫生至关重要.
研究的目的:
- 设计一种可溶性,高亲和度的ACE2诱蛋白,具有针对ACE2结合冠状病毒的广泛预防和治疗潜力.
- 识别特定的ACE2突变,增强与冠状病毒受体结合域 (RBDs) 的结合亲和力.
主要方法:
- 运用了计算 (in silico site-saturation mutagenesis) 和实验性蛋白质工程方法.
- 人类ACE2-冠状病毒RBD复合物的杆同质模型.
- 使用高通量方法生成和选ACE2突变体.
- 使用伪型病毒测定和人类呼吸道表皮细胞模型评估结合亲和力和中和能力.
主要成果:
- 确定了特定的ACE2残留替代物,显著增强了与SARS-CoV和SARS-CoV-2 RBDs的结合.
- 开发了ACE2-YHA,一种三重突变,明显改善了与SARS-CoV,SARS-CoV-2和蝙蝠SARSr-CoVs的结合亲和力.
- ACE2-YHA证明了SARS-CoV,多个SARS-CoV-2变体 (包括三角形和Omicron) 的强效中和,具有皮科莫尔IC50s.
- 在人类呼吸道上皮质模型中展示了有效的中和作用.
结论:
- ACE2-YHA是一种有前途的泛冠状病毒诱,具有增强的结合和强大的中和能力.
- 这种工程诱受体具有预防和治疗目前和未来由ACE2结合冠状病毒引起的疫情的巨大潜力.
- 该研究强调了结合计算和实验策略的有效性,以开发广泛的抗病毒疗法.
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