基于ACE2受体或工程化尖端结合的SARS-CoV-2进入抑制剂的比较
George N Llewellyn1, Hsu-Yu Chen1, Geoffrey L Rogers1
1Department of Molecular Microbiology and Immunology, Keck School of Medicine of the University of Southern California , Los Angeles, California, USA.
Journal of virology
|August 9, 2023
概括
新的SARS-CoV-2进入抑制剂,包括ACE2衍生品和工程,对抗耐药变种有希望. 一个优化的ACE2诱有效地中和了所有测试的变体,为抗体疗法提供了潜在的替代方案.
科学领域:
- 病毒学 病毒学
- 免疫学 免疫学 免疫学
- 药物发现 药物发现 药物发现
背景情况:
- 随着SARS-CoV-2变种对现有抗体疗法的耐药性增加,需要新的治疗策略.
- 开发针对重要病毒尖端蛋白区域的进入抑制剂为病毒耐药性提供了很高的障碍.
- 受体诱,如ACE2衍生物或工程,是有前途的治疗候选者.
研究的目的:
- 为了比较ACE2衍生物和Spike-binding作为SARS-CoV-2进入抑制剂的疗效.
- 为了评估这些抑制剂与各种SARS-CoV-2变体相对抗,包括对抗体耐药的抗体.
- 在临床前小鼠模型中评估优化抑制剂的治疗潜力.
主要方法:
- 构建了ACE2衍生物和Spike-binding作为对抗体Fc域的融合.
- 使用伪型和复制能力强的病毒对SARS-CoV-2变种进行了抑制疗效测试.
- 在人类ACE2转基因小鼠中评估的保护受到SARS-CoV-2Delta变体的挑战.
主要成果:
- 一种优化的ACE2衍生物在中和所有测试的SARS-CoV-2变种方面表现出高效.
- 尖结合显示出可变的活性,在Beta,Gamma和Omicron变体中观察到抗性.
- 在小鼠模型中,优化的ACE2和四重氨基抑制剂对Delta变异提供了部分保护.
结论:
- 优化的ACE2衍生物代表了广泛的SARS-CoV-2中和的有效策略.
- 工程可以有效,但可能需要优化 (例如,四重体形式) 来克服变体耐药性.
- Fc融合入口抑制剂显示出治疗潜力,可以作为SARS-CoV-2感染抗体疗法的替代方案.
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