The TMPRSS2 Inhibitor Nafamostat Reduces SARS-CoV-2 Pulmonary Infection in Mouse Models of COVID-19.
The TMPRSS2 Inhibitor Nafamostat Reduces SARS-CoV-2 Pulmonary Infection in Mouse Models of COVID-19.
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DOI：
10.1128/mbio.00970-21
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发表时间：
2021-08-31
期刊：
影响因子：
6.4
通讯作者：
McCray PB Jr
中科院分区：
文献类型：
--
作者：
Li K;Meyerholz DK;Bartlett JA;McCray PB Jr
2019冠状病毒病（COVID-19）大流行在全球范围内造成了严重的发病率和死亡率。病原体严重急性呼吸综合征冠状病毒2（SARS-CoV-2），当其刺突蛋白（S）与其受体血管紧张素转换酶2（ACE 2）结合时，启动宿主细胞进入。在气道上皮中，刺突蛋白被细胞表面蛋白酶TMPRSS 2切割，促进膜融合和进入细胞表面。这种对TMPRSS 2和相关蛋白酶的依赖性表明，蛋白酶抑制剂可能限制呼吸道中的SARS-CoV-2感染。在这里，我们测试了两种丝氨酸蛋白酶抑制剂，卡莫司他甲磺酸盐和萘莫司他甲磺酸盐，它们抑制SARS-CoV-2和第二种致病性冠状病毒中东呼吸综合征冠状病毒（MERS-CoV）进入的能力。卡莫司他和萘莫司他都减少了原代人气道上皮细胞和Calu-3 2B 4细胞系中的感染，其中萘莫司他表现出更大的效力。然后，我们使用两种小鼠模型评估萘莫司他是否对体内SARS-CoV-2具有保护作用。在通过人ACE 2转导对SARS-CoV-2感染致敏的小鼠中，在SARS-CoV-2感染之前或之后不久鼻内萘莫司他治疗显著降低了体重减轻和肺组织滴度。类似地，用萘莫司他预防性鼻内治疗减少了K18-hACE 2转基因小鼠的体重减轻、病毒负荷和死亡率。这些发现确立了萘莫司他作为预防或治疗SARS-CoV-2感染和疾病发病机制的候选药物。
The coronavirus disease 2019 (COVID-19) pandemic has caused significant morbidity and mortality on a global scale. The etiologic agent, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), initiates host cell entry when its spike protein (S) binds to its receptor, angiotensin-converting enzyme 2 (ACE2). In airway epithelia, the spike protein is cleaved by the cell surface protease TMPRSS2, facilitating membrane fusion and entry at the cell surface. This dependence on TMPRSS2 and related proteases suggests that protease inhibitors might limit SARS-CoV-2 infection in the respiratory tract. Here, we tested two serine protease inhibitors, camostat mesylate and nafamostat mesylate, for their ability to inhibit entry of SARS-CoV-2 and that of a second pathogenic coronavirus, Middle East respiratory syndrome coronavirus (MERS-CoV). Both camostat and nafamostat reduced infection in primary human airway epithelia and in the Calu-3 2B4 cell line, with nafamostat exhibiting greater potency. We then assessed whether nafamostat was protective against SARS-CoV-2 in vivo using two mouse models. In mice sensitized to SARS-CoV-2 infection by transduction with human ACE2, intranasal nafamostat treatment prior to or shortly after SARS-CoV-2 infection significantly reduced weight loss and lung tissue titers. Similarly, prophylactic intranasal treatment with nafamostat reduced weight loss, viral burden, and mortality in K18-hACE2 transgenic mice. These findings establish nafamostat as a candidate for the prevention or treatment of SARS-CoV-2 infection and disease pathogenesis.
DOI：
10.5090/kjtcs.2013.46.6.413
发表时间：
2013-12
期刊：
The Korean journal of thoracic and cardiovascular surgery
影响因子：
--
作者：
Yoon YS;Oh H;Kim Y;Lim SP;Kim CS;Kang MW
通讯作者：
Kang MW