一种TMPRSS2抑制剂作为泛SARS-CoV-2的预防和治疗
Tirosh Shapira1, I Abrrey Monreal2, Sébastien P Dion3
1Department of Microbiology and Immunology, Life Sciences Institute, University of British Columbia, Vancouver, British Columbia, Canada.
Nature
|March 28, 2022
概括
一种新的化合物N-0385通过向II型跨膜蛋白酶 (TTSPs) 有效抑制SARS-CoV-2感染. 这种小分子显示为早期治疗COVID-19及其新兴变种的有希望的选择.
科学领域:
- 病毒学
- 药理学
- 传染性疾病
背景情况:
- 由SARS-CoV-2引起的COVID-19仍然是一个全球健康危机.
- 疫苗的有效性受到新出现的SARS-CoV-2变种的挑战.
- 针对宿主的治疗方法提供了一种应对变异性耐药性的策略.
研究的目的:
- 识别和描述SARS-CoV-2进入的小分子抑制剂.
- 评估针对COVID-19治疗的II型跨膜蛋白酶 (TTSPs) 的潜力.
- 评估N-0385对SARS-CoV-2及其变种的疗效.
主要方法:
- 对SARS-CoV-2感染的抑制剂进行小分子查.
- 使用人类肺细胞 (Calu-3) 和结肠酸的体外测试.
- 在体内使用K18-人类ACE2转基因小鼠模型的COVID-19研究.
- 对N-0385对SARS-CoV-2变种 (阿尔法,贝塔,玛,三角形) 的抑制活性进行评估.
主要成果:
- 在抑制SARS-CoV-2方面,N-0385显示出低纳米分子效能和高选择性 (选择性指数> 10^6).
- 该化合物有效地抑制了细胞培养中多种令人担忧的SARS-CoV-2变体的进入.
- 在重症COVID-19的小鼠模型中,N-0385提供了显著的预防和治疗效益,即使是在单次给药后.
结论:
- 在体内对SARS-CoV-2感染至关重要的是TTSP介导的尖端蛋白质成熟.
- N-0385是SARS-CoV-2进入和病毒传播的强有力的抑制剂.
- N-0385代表了对抗COVID-19和新兴变种的有希望的早期治疗选择.
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